Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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Centriole structure DOI: 10.1098/rstb.2013.0457 Centrioles are among the largest protein-based structures found in most cell types, [...] Here, we briefly review ultra structural observations about centrioles and associated structures. At the core of most centrioles is a microtubule scaffold formed from a radial array of nine triplet microtubules. Beyond the microtubule triplets of the centriole, we discuss the critically important cartwheel structure and the more enigmatic luminal density, both found on the inside of the centriole. Finally, we discuss the connectors between centrioles, and the distal and subdistal appendages outside of the microtubule scaffold that reflect centriole age and impart special functions to the centriole. Significant opportunities remain in the description of centriolar structure, both in mapping of component proteins within the structure and in determining the effect of mutations on components that contribute to the structure and function of the centriole. http://rstb.royalsocietypublishing.org/content/369/1650/20130457
Work in progress... stay tuned.Dionisio_{May 20, 2015
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RBM14 prevents assembly of centriolar protein complexes and maintains mitotic spindle integrity DOI 10.15252/embj.201488979 The EMBO Journal (2015) 34, 97-114 Centrosome duplication is tightly orchestrated with cell cycle progression to yield the correct number of centrosomes Formation of a new centriole adjacent to a pre?existing centriole occurs only once per cell cycle. Despite being crucial for genome integrity, the mechanisms controlling centriole biogenesis remain elusive. How can RBM14 spatiotemporally limit the function of the STIL–CPAP complex? It is possible that RBM14 it is likely that RBM14 we speculate that RBM14 However, the formation of those structures was dependent on Plk4, suggesting that the assembly mechanism is different from what is shown in this study. Further study will be needed to describe the dynamics of the aberrant assembly of centriolar components in more detail and uncover the mechanisms by which they can assemble into substantial and functional structures to efficiently serve as MTOCs. [...] there could be a close linkage between the two assembly pathways for centriolar proteins. it will be important to investigate whether such aberrant assembly of centriolar proteins can be a cause of some types of cancer. http://emboj.embopress.org/content/34/1/97
Work in progress... stay tuned.Dionisio_{May 20, 2015
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The chromosomal passenger complex (CPC) as a key orchestrator of orderly mitotic exit and cytokinesis Front. Cell Dev. Biol., 2015 http://dx.doi.org/10.3389/fcell.2015.00014 Understanding the molecular network of orderly mitotic exit to re-establish a functional interphase nucleus is critical because disordered mitotic exit inevitably leads to genomic instability. In contrast to the mechanisms of the entrance to mitosis, however, little is known about what controls the orderly exit from mitosis, particularly in mammalian cells. These processes are tightly orchestrated by the opposing activities of protein kinases and phosphatases on mitotic chromosomes and in the cell equator, [...] These two events can be orchestrated by a set of master regulators, [...] The CPC also controls the timing of nuclear envelope reformation (NER), and finally in the midbody, the CPC controls the timing of abscission that completes cytokinesis How the CPC regulates and is regulated to execute these multiple mitotic events especially from the entrance into mitosis to anaphase onset has been extensively studied This change in localization is key for orchestrating the orderly mitotic exit [...] the chromosome adaptor that recruits MKLP2 is unknown. How the spatiotemporal recognition between MKLP2 and the CPC occurs on anaphase chromosomes remains unclear. it is unclear how this chromosome targeting of MKLP2 upon anaphase onset occurs before its mitotic spindle binding and bundling The reason why Cdk1/cyclin B1 phosphoregulates both MKLP2 and INCENP is unclear. it is unclear whether MKLP2 and Cdc48/p97 act in the same pathway for CPC relocation or whether they function independently to remove the CPC from anaphase chromosomes. It is unclear whether this mechanism is also conserved in mammalian cells, [...] The mechanisms how these events are temporally coordinated have just begun to emerge little is known about what controls chromatin decondensation after the exit from mitosis and in the early G1 phase the mechanism of chromosome decondensation with NER during mitotic exit is not well understood, it is debatable whether this surveillance mechanism functions as the chromosome separation checkpoint as suggested Further studies are needed to clarify the mechanisms of cell division plane specification it is unclear whether MKLP1, CHMP4C, and ANCHR-VPS4 act in the same pathway or whether they function independently downstream of Aurora B activity. An important question that remains to be resolved is how apparently different... It remains to be addressed whether Aurora B also governs the abscission timing that... Mitotic exit is a complex transition involving many dramatic cellular changes to occur in a coordinated manner. Future research is needed to investigate whether the CPC actively senses and signals to repair certain abnormalities of segregating sister chromatids or only passively delays an improperly executed mitotic exit event. It also remains to be determined how the CPC integrates and translates multiple phosphorylation events to determine the timing of abscission. http://journal.frontiersin.org/article/10.3389/fcell.2015.00014/full
Interesting stuff.Dionisio_{May 19, 2015
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Atypical centrioles during sexual reproduction Front. Cell Dev. Biol., 2015 http://dx.doi.org/10.3389/fcell.2015.00021 how animals gain their first two centrioles during reproduction is only partially understood. Our understanding and definition of a centriole changes as the technology employed to detect it improves. [in the future] technology should allow us to define a centriole based on relative localization of centriolar proteins. Defects in sperm centrioles, which affect their function in the zygote, are expected to result in male infertility; however, very little is known about this type of infertility. Also, we do not yet fully understand the structural and molecular mechanisms underlying the formation, modification, and maintenance of the various centriolar structures (i.e., PCL and degenerated centrioles) in the sperm and zygote. Therefore, directed studies are needed to precisely identify the centriole proteins and organization in the spermatozoa and zygote. Beyond gaining an essential understanding of fertilization, these studies will shed light on other basic questions and mechanisms in cell and developmental biology, such as centriole function, centriole duplication, and PCM formation. http://journal.frontiersin.org/article/10.3389/fcell.2015.00021/full
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Building a centriole doi:10.1016/j.ceb.2012.10.016 Centrioles are the key foundation of centrosomes and cilia, yet a molecular understanding of how they form has only recently begun to emerge. http://www.sciencedirect.com/science/article/pii/S0955067412001809
Dionisio_{May 18, 2015
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Asterless amplifies Plk4 JCB vol. 208 no. 4 382 The Rockefeller University Press, doi: 10.1083/jcb.2084iti1 the scaffold protein Asterless (Asl) regulates centriole duplication by controlling turnover of the kinase Plk4. how Asl overexpression drives centriole amplification is unknown. Asl affects Plk4 in multiple ways to regulate centriole duplication The authors now want to investigate how Asl is regulated throughout the cell cycle and how the stable Asl–Plk4 complexes are organized on the surface of centrioles. http://jcb.rupress.org/content/208/4/382.1.full
One question got answered, new interrogations have appeared. Unending revelation of the ultimate reality.Dionisio_{May 18, 2015
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Autoinhibition and relief mechanism* for Polo-like kinase 4 Proc Natl Acad Sci. 2015 E657-66. doi: 10.1073/pnas.1417967112. Polo-like kinase 4 (Plk4) is a master regulator* of centriole duplication, and its hyperactivity induces* centriole amplification. Homodimeric Plk4 has been shown to be ubiquitinated as a result of* autophosphorylation, thus promoting* its own degradation and preventing* centriole amplification. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Here, we performed a functional analysis of Plk4's structural domains. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated* by a linker (L1) near the kinase domain. Thus, autoinhibition is a conserved feature of Plks. In the case of Plk4, autoinhibition is relieved* after homodimerization and is accomplished* by PB3 and by autophosphorylation of L1. In contrast, autophosphorylation of the second linker promotes* separation of the Plk4 homodimer. Therefore, autoinhibition delays* the multiple consequences of activation until* Plk4 dimerizes. These findings reveal a complex mechanism of Plk4 regulation and activation which govern* the process of centriole duplication. http://www.ncbi.nlm.nih.gov/pubmed/25646492
(*) how? (spatiotemporal detailed description required) As much deeper research is done and newer discoveries are made, the big picture of the elaborate cellular and molecular choreographies orchestrated within the biological systems look amazingly interesting. That’s why I look forward, with much anticipation, to reading future research papers shedding more light on all these information-processing interwoven complexities.Dionisio_{May 18, 2015
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The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis doi: 10.1242/?jcs.166496 J Cell Sci 128, 1674-1682. effective control of centriole numbers is essential for embryogenesis, tissue homeostasis and genome stability Mib1 localizes to centriolar satellites but redistributes to centrioles in response to conditions that induce centriole amplification. The E3 ligase activity of Mib1 triggers ubiquitylation of Plk4 on multiple sites, causing the formation of Lys11?, Lys29? and Lys48?ubiquitin linkages. These modifications control the abundance of Plk4 and its ability to interact with centrosomal proteins, thus counteracting centriole amplification induced by excess Plk4. Collectively, these results identify the interaction between Mib1 and Plk4 as a new and important element in the control of centriole homeostasis. http://jcs.biologists.org/content/128/9/1674.abstract
A few things going on there...Dionisio_{May 18, 2015
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Plk4-dependent phosphorylation of STIL is required for centriole duplication doi: 10.1242/?bio.201411023 Biology Open 4, 370-377. However, it remains unclear from their study whether a fragment comprising PB1 and PB2 is able to bind to STIL. Our findings therefore suggest that Plk4 harbors a so far undiscovered substrate binding domain that is located between the catalytic domain and the polo-box domain. This observation implicates that Plk4 also exerts another function independent from its localization to the centrioles. As the STAN domain has been implicated in centriole duplication, we speculate that in particular phosphorylation on S1116 is involved in centrosome amplification. Future studies will be required to demonstrate how and when during the early cell cycle stages phosphorylation of STIL by Plk4 will initiate procentriole formation. http://bio.biologists.org/content/4/3/370.full
As much deeper research is done and newer discoveries are made, the big picture of the elaborate cellular and molecular choreographies orchestrated within the biological systems look amazingly interesting. That's why I look forward, with much anticipation, to reading future research papers shedding more light on all these information-processing complexity.Dionisio_{May 18, 2015
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Kinetochore flexibility: creating a dynamic chromosome–spindle interface doi:10.1016/j.ceb.2011.12.008 Kinetochores are complex macromolecular assemblies that link chromosomes to the mitotic spindle, mediate forces for chromosome motion, and generate the checkpoint signal delaying anaphase onset until all chromosomes are incorporated into the spindle. Proper execution of these functions depends on precise interactions between kinetochores and microtubules. While the molecular composition of the kinetochore is well described, structural organization of this organelle at the molecular and atomic levels is just beginning to emerge. Recent structural studies across scales suggest that kinetochores should not be viewed as rigid static scaffolds. Instead, these organelles exhibit a surprising degree of flexibility that enables rapid adaptations to various types of interactions with the mitotic spindle. http://www.sciencedirect.com/science/article/pii/S0955067411001700
surprising? Why?Dionisio_{May 17, 2015
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Interesting research paper:
Empirical neuroenchantment: from reading minds to thinking critically Front. Hum. Neurosci., 2014 http://dx.doi.org/10.3389/fnhum.2014.00357 http://journal.frontiersin.org/article/10.3389/fnhum.2014.00357/full
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Criticality as a signature of healthy neural systems Front. Syst. Neurosci., 2015 http://dx.doi.org/10.3389/fnsys.2015.00022
The hypothesis that brain activity, or specifically, neuronal activity in the cortex, might be critical arose from the premise that a critical brain can show the fastest and most flexible adaptation to a rather unpredictable environment
if the brain works close to or at a critical point, it is interesting to investigate the role of criticality on cognition and long-term temporal correlations observed in behavioral studies little is known about the causes and/or consequences of a loss of criticality, and its relation with brain diseases
The study of how pathogenic mechanisms are related to the critical/non-critical behavior of neuronal networks would likely provide new insights into the cellular and synaptic determinants supporting the emergence of critical-like dynamics and structures in neural systems.
the relationship between disrupted criticality and impaired behavior would help clarify the role of critical dynamics in normal brain functioning existing models lack precise physiological descriptions for how the brain maintains its tuning near a critical point. a missing fundamental ingredient is a formulation of the reciprocal coupling between neural activity and metabolic resources
The hypothesis that cortical dynamics resides at a critical point, at which information processing is optimized, has refocused attempts to explain the tremendous variability in neuronal activity patterns observed in the brain at all scales.
http://journal.frontiersin.org/article/10.3389/fnsys.2015.00022/full
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Substrate recognition and function of the R2TP complex in response to cellular stress Front. Genet., 2015 http://dx.doi.org/10.3389/fgene.2015.00069 Although the R2TP complex has become recently focus of many studies, the exact function and the molecular mechanism of its action is still not clear. Assembly of snoRNPs is a complicated process, which requires a number of assembly factors. Although the work on snoRNPs assembly provides some clues about the mechanism of the R2TP complex function, most of it is still largely unknown. Although the R2TP complex is also involved in regulation of DNA damage response, it is not known whether the DNA damage signaling affects localization or assembly of the R2TP complex.
In order to protect genome integrity, cells are equipped with an extensive response mechanism that comes into play after DNA damage. The general mechanism of the DNA damage response consists of sensors, transducers, and effectors.
The role of RUVBL1/2 in all the mentioned complexes is unknown The mechanisms by which the R2TP complex recognizes its substrates and exerts its function are still not completely understood. Most of R2TPs functional mechanisms still remain elusive:
how does R2TP assert its function on its substrates? What is the role of the prefoldin/like complexes associated with the R2TP complex? Are the differences in the structures reported for the RUVBL hexameres relevant for its function? What is the role of HSP90 in the R2TP complex? Is the PIH-N domain always involved in R2TP substrate recognition? Is PIH-N domain involved in regulating assembly processes? Is the R2TP complex generally involved in assembly of complexes containing RUVBL1/2?
Answering these questions will allow us to start understanding of the molecular mechanisms of the function of this highly important complex. http://journal.frontiersin.org/article/10.3389/fgene.2015.00069/full
I like the last statement:
Answering these questions will allow us to start understanding of the molecular mechanisms of the function of this highly important complex.
They didn't say "Answering these questions will allow us to understand..." but "...to start understanding..." That denotes humility in their research approach.Dionisio_{May 16, 2015
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How the cell cycle impacts chromatin architecture and influences cell fate Front. Genet., http://dx.doi.org/10.3389/fgene.2015.00019 Extensive connections between the cell cycle machinery and chromatin clearly exist, which impact gene expression and thus, cell fate decisions in important ways. several key questions remain unresolved. For example, does the gene expression profile of a cell, and thus cell fate, control important facets of the cell cycle such as origin choice and DNA replication timing? Or does the cell cycle status of a cell instead determine its gene expression possibilities and therefore limit choices in cell fate? If the latter is true, how can cell fate be so robustly maintained in some instances of regeneration or in cases of cell cycle disruption during development? As we learn more about the truly plastic nature of cell fate, we expect to find that the cell cycle influences the probability of acquiring certain cell fate programs, but that multiple cell cycle and cell fate states can be compatible under specific conditions. Future work will continue to uncover new molecular connections between the cell cycle machinery and developmental signaling pathways, to help us finally understand how the cell cycle impacts cell fate. http://journal.frontiersin.org/article/10.3389/fgene.2015.00019/full
I don't like any gaps in biological knowledge. I enjoy reading about new discoveries. That's why I look forward, with much anticipation, to reading newer research papers that will shed more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems. I pray that God gives abundant wisdom to the scientists and reveals more mysteries to them, according to the purpose of His will and for His glory, as the researchers continue their challenging work in the days ahead. In the meantime, while we wait for the next revelations, let's sing hallelujah!Dionisio_{May 16, 2015
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Nervous decision-making: to divide or differentiate DOI: http://dx.doi.org/10.1016/j.tig.2014.04.001 Further work is required to elucidate the nature and associated mediators of changes in the epigenetic landscape, but this may contribute to our understanding of tissue- or stage-specific gene expression profiles. Future studies may include a greater characterisation of cell cycle-regulated post-translational modifications of key differentiation factors, coupled with genome-wide analysis of transcription factor activity in proliferating and differentiating cells. These are likely to reveal the mechanistic basis behind at least some of the many interactions between the cell cycle and differentiation machinery, and they may also explain further the context-dependent activity of key regulators, such as the proneural proteins. Such insights will surely have far-reaching implications in our understanding of the developing nervous system, in treatment of neurological disorders and cancers, and in advancing our ability to use regenerative medicine to replace lost neurons in conditions such as stroke and spinal cord injury. http://www.cell.com/trends/genetics/fulltext/S0168-9525(14)00055-9
A few questions remain.Dionisio_{May 15, 2015
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Cell cycle regulation of proliferation versus differentiation in the central nervous system Cell and Tissue Research 10.1007/s00441-014-1895-8 http://link.springer.com/article/10.1007/s00441-014-1895-8/fulltext.html despite their central importance in developmental events, mechanisms ensuring precise coordination between cell division, cell cycle exit and differentiation have remained obscure until relatively recently. Despite the great progress made in this area in recent years, we still have a lot to learn, with important implications for the fields of developmental biology, regenerative medicine and oncology, among others; this promises to be an exciting field over the coming decade.
Work in progress... stay tuned. :)Dionisio_{May 15, 2015
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#423 addendum
An oblique view on the role of spindle orientation in vertebrate neurogenesis DOI: 10.1111/j.1440-169X.2012.01350.x Development, Growth & Differentiation Special Issue: Neural Development Edited by T. Miyata. Volume 54, Issue 3 http://onlinelibrary.wiley.com/doi/10.1111/j.1440-169X.2012.01350.x/full Over the last decade, the description of the diversity of neural progenitors in the developing nervous system and particularly in the mammalian neocortex has made tremendous progress. In parallel, our understanding of the mechanisms regulating the fate choices that control the balance between these different populations has also improved, but it remains fragmentary. A number of fate determinants have been proposed, and it is not yet possible to reconcile all the observations in one single coherent model of neurogenesis progression. It is also very likely that fate determination consists of many superimposed layers of molecular decisions, none of which result in binary choices, and whose particular combination increases the chances of a cell to go along a particular path. Regarding the specific question of spindle orientation, there is currently little convincing evidence for a direct implication in fate decisions based on a classical mechanism of intrinsic asymmetric division. Clearly, identifying these signals and understanding how they are integrated in space and time, will require many years of exciting research.
This was about 3 years ago. Maybe by now some of those issues have been resolved? I look forward, with much anticipation, to reading newer research papers that will shed more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems.Dionisio_{May 15, 2015
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An oblique view on the role of spindle orientation in vertebrate neurogenesis DOI: 10.1111/j.1440-169X.2012.01350.x Development, Growth & Differentiation Special Issue: Neural Development Edited by T. Miyata. Volume 54, Issue 3 http://onlinelibrary.wiley.com/doi/10.1111/j.1440-169X.2012.01350.x/full Understanding the molecular mechanisms regulating the choice between symmetric and asymmetric modes of division is essential to understand human brain development and pathologies, and to explain the increasing cortical complexity The question of the regulation of the choice between symmetric and asymmetric divisions has been the focus of intense efforts in the last two decades Despite this strong interest, how this balance is regulated is still poorly understood at the molecular level, and as we will see in this review, it is likely a complex, multifactorial process that integrates a number of cell autonomous and cell extrinsic information.
Dionisio_{May 15, 2015
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Interkinetic nuclear migration generates and opposes ventricular-zone crowding: insight into tissue mechanics Front. Cell. Neurosci., 2015 | http://dx.doi.org/10.3389/fncel.2014.00473 http://journal.frontiersin.org/article/10.3389/fncel.2014.00473/full future studies using mechanobiological approaches should be able to elucidate how a non-PS (non-VZ) proliferative zone for stem-like cells have arisen during neocortical evolution. future studies should attempt to determine whether cleavage orientation is regulated by tissue-level mechanical factors or through VZ densification. Physiological delamination is exhibited by neocortical VZ cells that have acquired non–stem-like (differentiation) properties Whether this process is also mechanically regulated, as speculated by Smart (1973), is another question that should be addressed experimentally. Application of such experimental methods, coupled with quantitative measurement of mechanical forces, will deepen our understanding of both physiological and pathological delimitation. we are still far from understanding how INM behaviors of all VZ cells are coordinated such that they are not abnormally synchronized, in terms of both cell-cycle progression and nucleokinesis. A combination of cell-biological experiments and in silico simulations should help to address this community-level question in vivo.
Work in progress... a few minor questions remain...Dionisio_{May 15, 2015
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p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex doi: 10.1242/?bio.20147807 Biology Open 3, 475-485. http://bio.biologists.org/content/3/6/475.full Because these results were obtained in an artificial system (i.e. HeLa cells), further studies are required to substantiate these findings. A complete understanding of the mechanism by which p600 and Ndel1 interact to control spindle orientation will also require us to localize the functional domains of p600 with greater accuracy and to test the above hypothesis biochemically and in neural progenitors. The dearth of data on the localization of functional domains and post-translational modifications within p600 denies us the opportunity to focus on likely areas. This absence of probable targets, combined with the humongous size of p600 and the variable solubility of the relevant C-terminal regions, make the full characterization of the p600/Ndel1 interaction by domain-mapping or mutagenesis an unusually daunting task, and drive it out of the scope of this paper. Further study of p600 in NP populations will provide a better understanding of the roles of p600 in cell fate determination and neurogenesis in the developing and adult brain.
Dionisio_{May 14, 2015
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Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes Open Cell Death and Disease (2015) 6, e1700; doi:10.1038/cddis.2015.67 Future studies are required to understand how lincRNA-p21 is repressing and activating gene expression in keratinocytes in response to UVB treatment. further studies in lincRNA-p21 knockout keratinocytes will be required to address method of depletions and whether lincRNA-p21 functions in cis or trans to regulate gene expression in UVB-treated keratinocytes. The etiology of most chronic human diseases involves complex interactions among environmental factors and an individual's genetic and epigenetic makeup. However, these gene × environment interactions are poorly understood, leading to a deficit in our understanding of how these interactions contribute to adverse health outcomes. http://www.nature.com/cddis/journal/v6/n3/full/cddis201567a.html
Dionisio_{May 14, 2015
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Integration of Genome-wide Approaches Identifies lncRNAs of Adult Neural Stem Cells and Their Progeny In Vivo doi:10.1016/j.stem.2013.03.003 Long noncoding RNAs (lncRNAs) have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. lncRNAs can play key roles in the glial-neuronal lineage specification of multipotent adult stem cells. Taken together, our genome-wide analysis and functional data further support the notion that lncRNAs and homeobox gene neighbors function cooperatively A recent model of lncRNA action suggests that lineage-specific lncRNAs become activated during differentiation and guide histone modifications that create cell type-specific transcriptional programs our data raise the possibility that lncRNA loci, like protein-coding genes, are targeted by chromatin-modifying factors that have critical roles in development. While this study attempted to be as comprehensive as possible, it is possible that some lncRNAs important for SVZ neurogenesis were not identified. we were still able to identify thousands of previously unannotated lncRNA transcripts. The role of lncRNAs in development and disease is in the early states of investigation, and our analysis of the SVZ lineage provides a resource for the movement of this research into in vivo studies. More broadly, this work presents a generalizable workflow for the identification and categorization of novel transcripts, both coding and noncoding. http://www.sciencedirect.com/science/article/pii/S1934590913000982
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Junk DNA and the long non-coding RNA twist in cancer genetics Oncogene , (26 January 2015) doi:10.1038/onc.2014.456 H Ling, K Vincent, M Pichler, R Fodde, I Berindan-Neagoe, F J Slack and G A Calin The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer. http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2014456a.html
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An Epigenomic Road Map for Endoderm Development doi:10.1016/j.stem.2015.03.006 While studies of organ development have traditionally relied on model organisms, recent advances in embryonic stem cell (ESC) culture allow investigation of organogenesis in human cells. Wang et al. (2015) employ this system to map the dynamic enhancer landscape during ESC differentiation to the endoderm derivatives pancreas and liver. http://www.sciencedirect.com/science/article/pii/S1934590915001174
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Long Non-Coding RNAs Control Hematopoietic Stem Cell Function doi:10.1016/j.stem.2015.02.002 Hematopoietic stem cells (HSCs) possess unique gene expression programs that enforce their identity and regulate lineage commitment. Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression and cell fate decisions, although their functions in HSCs are unclear. Together, these results demonstrate that lncRNAs play important roles in regulating HSCs, providing an additional layer to the genetic circuitry controlling HSC function. http://www.sciencedirect.com/science/article/pii/S1934590915000582
Dionisio_{May 14, 2015
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The lncRNA Pnky in the Brain doi:10.1016/j.stem.2015.03.015 Long noncoding RNAs (lncRNAs) influence diverse cellular processes and have been implicated in regulating stem cell properties. Now in Cell Stem Cell, Ramos et al. (2015) demonstrate that the neural-specific lncRNA Pnky regulates neuronal differentiation from neural stem cells and mediates RNA splicing through interactions with polypyrimidine tract-binding protein 1 (PTBP1). http://www.sciencedirect.com/science/article/pii/S1934590915001265
Dionisio_{May 14, 2015
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The Long Noncoding RNA Pnky Regulates Neuronal Differentiation of Embryonic and Postnatal Neural Stem Cells doi:10.1016/j.stem.2015.02.007 While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing gregulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations. http://www.sciencedirect.com/science/article/pii/S1934590915000636
Dionisio_{May 14, 2015
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Junk DNA and the long non-coding RNA twist in cancer genetics Oncogene. 2015 Jan 26. doi: 10.1038/onc.2014.456 The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual's susceptibility to cancer.Oncogene advance online publication, 26 January 2015; doi:10.1038/onc.2014.456. http://www.ncbi.nlm.nih.gov/pubmed/25619839
Dionisio_{May 13, 2015
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Pseudogene-derived lncRNAs: emerging regulators of gene expression Front. Genet., 04 February 2015 | http://dx.doi.org/10.3389/fgene.2014.00476 In the more than one decade since the completion of the Human Genome Project, the prevalence of non-protein-coding functional elements in the human genome has emerged as a key revelation in post-genomic biology. Pseudogene transcription and function remain insufficiently understood. Redefining the Human Gene Count The fact that non-coding genes are so ubiquitous makes it reasonable to hypothesize that their ncRNA products may be extensively involved in the regulation of protein-coding genes. In fact, evidence in favor of specific lncRNAs’ regulatory inputs into particular protein-coding genes is emerging Long Non-Coding RNA: Structure, Identification, and Function the vast majority of individual lncRNA mechanisms remain unknown. Pseudogene Structure and Function Recently, Gencode has developed a distinct and hierarchical set of biotypes describing pseudogenes and differentiating them from protein-coding genes comprehensive comparisons of lncRNA promoter and exon conservation genomewide in other lineages have still not been performed. lncRNA Transcription Regulating Pseudogenes the still-emerging lncRNA-pseudogene regulation field is marked by a paucity of experimentally validated examples synergistic gene regulation by pseudogenes and lncRNAs needs to be considered as a novel regulatory mechanism. Despite this evidence for lncRNA and pseudogene function on a case by case basis, there is still a generalized dearth of expressed pseudogene functional support, particularly within the genomewide context of pseudogene overlaps with lncRNA genes. lncRNAs overlapping with pseudogenes are also a potential contributor to both the magnitude and the directionality of this regulation. numerous additional examples of joint lncRNA- and pseudogene-driven regulation of protein-coding genes are waiting to be discovered in post-genomic datasets. The rapidly growing datasets of significantly disease-associated SNPs from Genome-Wide Association Studies, a resource that has empowered the realization that most trait-associated loci are not protein-coding, are likely to provide a goldmine of intrapseudogenic and lncRNA exonic disease-associated SNPs which can then pave the way to functional studies for decades to come. http://journal.frontiersin.org/article/10.3389/fgene.2014.00476/full
Dionisio_{May 13, 2015
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Pseudogenes: Pseudo or Real Functional Elements? doi:10.1016/j.jgg.2013.03.003 Although broadly existed, pseudogenes used to be considered as junk or relics of genomes which have not drawn enough attentions of biologists until recent years. growing lines of evidence have strongly suggested that some pseudogenes possess special functions, including regulating parental gene expression and participating in the regulation of many biological processes. pseudogenes are not purely dead fossils of genomes, but warrant further exploration in their distribution, expression regulation and functions. A new nomenclature is desirable for the currently called ‘pseudogenes’ to better describe their functions. http://www.sciencedirect.com/science/article/pii/S1673852713000568
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