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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Comments

[...] DNA methylation, as a bona fide epigenetic marker, is not only inheritable and dynamic, but also involved in diverse regulatory processes.
Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

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[...] work in this field will yield additional layers of both chemical and biological complexity as we continue to uncover functional consequences of known nucleic acid modifications and discover new ones.
Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

Complex complexity.Dionisio_{April 4, 2017
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RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (m6A), inosine (I), pseudouridine (?) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the m6A modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle.
Epitranscriptomic regulation of viral replication. Pereira-Montecinos C, Valiente-Echeverría F, Soto-Rifo R Biochim Biophys Acta. 1860(4):460-471. doi: 10.1016/j.bbagrm.2017.02.002.

Complex complexity.Dionisio_{April 4, 2017
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The first chemical modification to RNA was discovered nearly 60 years ago; to date, more than 100 chemically distinct modifications have been identified in cellular RNA. With the recent development of novel chemical and/or biochemical methods, dynamic modifications to RNA have been identified in the transcriptome, including N6-methyladenosine (m6A), inosine (I), 5-methylcytosine (m5C), pseudouridine (?), 5-hydroxymethylcytosine (hm5C), and N1-methyladenosine (m1A). Collectively, the multitude of RNA modifications are termed epitranscriptome, leading to the emerging field of epitranscriptomics.
Chemical Modifications to RNA: A New Layer of Gene Expression Regulation. Song J, Yi C ACS Chem Biol. 12(2):316-325. doi: 10.1021/acschembio.6b00960.

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[...] the primary challenges for cellular and molecular biologists to still explore. One of these challenges is to elucidate more fully the mechanisms involved in the specification of the corneal epithelium. A major challenge [...] will be to find an early molecular marker for corneal fate. [...] it will be interesting to compare the inducing potential of corneal epithelium versus that of the oral epithelium. It will be interesting to know the result of the interaction with a “naïve mesenchyme,” as it might differ from that which occurs when the CE is associated with an embryonic dermis. [...] there is a distinct shift in the clonal composition of the cornea during the course of development, which reflects a change in the localisation of the corneal stem cells as the organisms develop and age [...] These open questions, together with the increasing numbers of molecular tools available, make this an exciting time to study the development and renewal of corneal epithelium. A deeper understanding of these mechanisms will certainly aid us make significant advances in clinical applications.
The Vertebrate Corneal Epithelium: From Early Specification to Constant Renewal Danielle Dhouailly, David J. Pearton and Frederic Michon3 DEVELOPMENTAL DYNAMICS DOI: 10.1002/DVDY.24179

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Much of the recent focus has been directed towards understanding the early development of the cornea and its renewal mechanisms as a step towards applications in regenerative medicine. Much work, however, remains but the use of cellular, molecular, and genetic approaches will enable continued progress.
The Vertebrate Corneal Epithelium: From Early Specification to Constant Renewal Danielle Dhouailly, David J. Pearton and Frederic Michon3 DEVELOPMENTAL DYNAMICS DOI: 10.1002/DVDY.24179

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The cornea is an ectodermal/neural crest derivative formed through a cascade of molecular mechanisms to give rise to the specific optical features necessary for its refractory function. Moreover, during cornea formation and maturation, epithelial stem cells are sequestered to ensure a constant source for renewal in the adult. While the embryonic origin as well as the localization of stem cells for most other ectodermal organs has been studied in depth, in the case of the cornea these two major questions are still under debate.
The Vertebrate Corneal Epithelium: From Early Specification to Constant Renewal Danielle Dhouailly, David J. Pearton and Frederic Michon3 DEVELOPMENTAL DYNAMICS DOI: 10.1002/DVDY.24179

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The advent of next-generation sequencing techniques [...] should technically enable researchers to tie together the transcriptional networks, the chromatin regulators and the enhancer elements that are key in cortical development. [...] Pax6 is only one of many key TF for cortical development. Integrating the information garnered for each TF into a coherent model will indubitably be a major goal and hurdle in our understanding of cortical developmental processes. Major concerted efforts to determine the epigenetic marks present in different cell types at different time points, such as the large-scale project currently being carried out by ENCODE, are undeniably going to enable the community to begin understanding TF networks in the context of their epigenetic environment. Moreover, other efforts designed to systematically track down enhancers active in cortical tissue in development will also provide greatly needed resources for the neuroscience community
Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Work in progress... stay tuned. Complex complexity.Dionisio_{April 4, 2017
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It will be important to determine the gene regulatory networks important for conferring appropriate patterning to the cortex as it develops. Currently, much work remains to understand the transcriptional network required to propagate patterning information from the VZ to the cortical plate, and an even more arduous enterprise will be required in identifying the cis-regulatory elements at play in this complex developmental process.
Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Work in progress... stay tuned. Complex complexity.Dionisio_{April 4, 2017
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The mammalian cortex is a region with an exceedingly complicated cytoarchitecture. Distinct regions of the adult cortex execute discrete cortical functions (i.e. visual processing) that are central to cognition. Moreover, it is organized into six layers, which differ in their cellular constituents and connectivity. The cortex possesses two main categories of neurons: excitatory projection neurons, that extend their axons over long distances to cortical and subcortical targets; and inhibitory interneurons, which generally have short axons and regulate local circuits. Excitatory neurons are generated by cortical progenitors, whereas inhibitory neurons are generated by subcortical progenitors in the ganglionic eminences.
Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Complex complexity.Dionisio_{April 4, 2017
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The development of the cortex is an elaborate process which integrates a plethora of finely tuned molecular processes ranging from carefully regulated gradients of transcription factors, dynamic changes in the chromatin landscape or formation of protein complexes to elicit and regulate transcription. Combined with cellular processes such as cell type specification, proliferation, differentiation and migration, all of these developmental processes result in the establishment of an adult mammalian cortex with its typical lamination and regional patterning.
Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Complex complexity. Note: this interesting paper reference was graciously provided by gpuccio in another discussion thread: https://uncommondescent.com/intelligent-design/gp-on-the-origin-of-body-plans-oobp-challenge/#comment-628278Dionisio_{April 4, 2017
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In conclusion, this study identifies a genetic requirement for Meis1 and Meis2 for early steps of mammalian eye development and reveals an apparent robustness of the gene regulatory mechanism whereby two independent "shadow enhancers" of similar molecular architecture maintain critical levels of a dosage-sensitive gene, Pax6, during lens induction. These results allow us to establish a genetic hierarchy during early vertebrate eye development and provide novel mechanistic insights into the regulatory logic of this process.
The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

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[...] it is very likely that Meis1 and Meis2 fulfill the redundant function only in specific developmental stages and processes [...] while having many discrete functions in the embryo even within the eye development.
The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

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GRNs provide a system level explanation of development in terms of the genomic regulatory code [...] While significant insights into the functional role of many transcription factors during the lens placode formation have been realised, much less is known about the upstream regulation of these critical factors and the intricate wiring of the GRN that controls the earliest stages of lens development.
The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity.Dionisio_{April 4, 2017
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Remarkably, our data demonstrate the existence of two independent and partially redundant Meis-dependent enhancers, with similar molecular architecture, involved in the regulation of Pax6 expression during lens placode formation, thereby providing an unexpected level of robustness to the system.
The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Did somebody say "unexpected"? :) Complex complexity.Dionisio_{April 4, 2017
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While significant insights into the functional role of some transcription factors during lens formation have been accomplished, much less is known about the intricate wiring of the gene regulatory network (GRN) that controls the earliest stages of lens development.
The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity.Dionisio_{April 3, 2017
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Lens induction is a classical developmental model allowing investigation of cell specification, spatiotemporal control of gene expression, as well as how transcription factors are integrated into highly complex gene regulatory networks (GRNs). Pax6 represents a key node in the gene regulatory network governing mammalian lens induction. Meis1 and Meis2 homeoproteins are considered as essential upstream regulators of Pax6 during lens morphogenesis based on their interaction with the ectoderm enhancer (EE) located upstream of Pax6 transcription start site.
The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity.Dionisio_{April 3, 2017
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This chaos existing in naming method causes the difficulty of circRNA classification. A normative and widely accepted naming system is necessary.
Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

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What will happen to miRNAs after their release in a inactive state from the cleaved circRNAs? What contributes do the interaction between circRNA, miRNA and their parental gene serves in the process of aging and functional organ degeneration? These questions are all worthy of further study. Maybe someday humans can unveil the mystery of aging by researching these promising RNAs.
Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity.Dionisio_{April 3, 2017
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[...] the function of large amounts of circRNAs which have been detected inside animal cells still remains largely unknown and awaits further detailed study.
Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

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Brain circRNAs are suggested to regulate synaptic function and go hand in hand with the development of nervous system, this important discovery adds further dimension to our understanding of the molecular pervasiveness and importance of circular RNAs.
Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

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The regulating role of circRNAs is not isolated but through an enormous complicated network involving mRNAs, miRNAs and proteins. [...] most of the potential functions still remain unclear [...]
Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

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Accumulating studies were performed to explore the expression profile of circRNAs in different cell types and diseases, the outcomes totally changed our view of ncRNAs, which was thought to be junk by-products in the process of gene transcription, and enriched our poor understanding of its underlying functions.
Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

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Intense efforts are underway to elucidate the functions of circRNAs. [...] circRNAs are widely believed to influence mRNA metabolism on many levels (transcription, splicing, mRNA turnover, translation) [...] The ongoing efforts to elucidate circRNA function must include these considerations as they will illuminate more fully the rich and versatile impact of circRNAs in physiology and pathology.
Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

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The biogenesis of circRNAs is not fully understood [...] [...] more than one type of circRNA containing exon(s), intron(s), or both can be produced from a single gene. It will be particularly important to establish more comprehensively whether subsets of circRNAs associate with polysomes and might be translated.
Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

Complex complexity.Dionisio_{April 3, 2017
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Circular RNAs (circRNAs) comprise a family of noncoding RNAs (ncRNAs) that have drawn intense interest in the last few years. Although they were first discovered in 1979 by electron microscopy, they were thought to be byproducts of splicing and did not receive much attention due to their low abundance and lack of known functions.
Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

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Circular RNAs (circRNAs) represent a large class of noncoding RNAs (ncRNAs) that have recently emerged as regulators of gene expression. They have been shown to suppress microRNAs, thereby increasing the translation and stability of the targets of such microRNAs. The ensuing changes in gene expression patterns elicited by circRNAs are proposed to drive key cellular processes, such as cell proliferation, differentiation, and survival, that govern health and disease.
Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

Complex complexity.Dionisio_{April 3, 2017
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Determining the function, if any, of the thousands of circRNAs expressed across the tree of life will likely occupy researchers for years to come. The abundance of circRNA and the significant sequence overlap with mRNA or linear ncRNA transcribed from the same locus pose technical and conceptual challenges to studies of circRNA regulation and function that the field will have to address [...]
Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

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[...] circRNA from both protein-coding and noncoding genes are alternatively spliced through exon skipping and, in some cases, through intron inclusion, and regulated in a cell type-specific manner [...] [...] the processes underlying this regulation are not yet well understood [...]
Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

What else is new? Complex complexity.Dionisio_{April 3, 2017
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Given its prevalence and the fact that it was overlooked until very recently, circRNA warrants attention from essentially all molecular biologists.
Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Did somebody say "overlooked until very recently"? :) Why did it take them that long to look at it? Complex complexity.Dionisio_{April 2, 2017
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