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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[...] these discoveries suggest greater complexity, regulation, and function of complex eukaryotic gene expression, as well as begging many significant and fundamental questions about the role of circRNA in the cell. Much work remains to be done in this area, which is now very active.
Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Complex complexity.Dionisio_{April 2, 2017
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[...] circRNA production has either been conserved over billions of years or else is a feature that has re-evolved multiple times; either implies a likely functional role for circRNAs in the cell.
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 "re-evolved multiple times"? Is the term "re-evolved" associated with the word revolver? :) Complex complexity.Dionisio_{April 2, 2017
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In 2012, a statistical analysis of RNA-Seq data and subsequent biochemical analysis revealed a complete surprise: circRNA (see Glossary) molecules transcribed and spliced from exons in protein and noncoding genes are ubiquitous in the human and mouse genomes and, thus, are likely to be a pervasive and previously overlooked feature of eukaryotic gene expression and regulation [...]
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 "revealed a complete surprise"? :) Why were they so surprised? What did they expect? Did somebody say "previously overlooked feature"? :) Why did they overlook it? Could it be because they are doing bottom-up reductionist reverse-engineering research? Complex complexity.Dionisio_{April 2, 2017
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In 2012, a new feature of eukaryotic gene expression emerged: ubiquitous expression of circular RNA (circRNA) from genes traditionally thought to express messenger or linear noncoding (nc)RNA only. CircRNAs are covalently closed, circular RNA molecules that typically comprise exonic sequences and are spliced at canonical splice sites. This feature of gene expression was first recognized in humans and mouse, but it quickly emerged that it was common across essentially all eukaryotes studied by molecular biologists. CircRNA abundance, and even which alternatively spliced circRNA isoforms are expressed, varies by cell type and can exceed the abundance of the traditional linear mRNA or ncRNA transcript. CircRNAs are enriched in the brain and increase in abundance during fetal development. Together, these features raise fundamental questions regarding the regulation of circRNA in cis and in trans, and its function.
Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Complex complexity.Dionisio_{April 2, 2017
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Nucleus is the residence and place of work for a plethora of long noncoding RNAs. Here, we provide a summary of the functions and functional mechanisms of several relatively well studied examples of nuclear long noncoding RNAs (lncRNAs) in the nucleus, such as Xist, NEAT1, MALAT1 and TERRA. The recently identified novel EIciRNA is also highlighted. These nuclear lncRNAs play a variety of roles with diverse molecular mechanisms in animal cells. We also discuss insights and concerns about current and future studies of nuclear lnc RNAs.
Functions of long noncoding RNAs in the nucleus Bin Yu & Ge Shan? Journal Nucleus ? Volume 7, 2016 - Issue 2 DOI: 10.1080/19491034.2016.1179408

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Circadian clocks regulate rhythmic gene expression levels by means of mRNA oscillations that are mainly driven by post-transcriptional regulation. Major components of paraspeckles including the long noncoding RNA Neat1, which is the structural component, and its major protein partners, as well as the number of paraspeckles, follow a circadian pattern in pituitary cells. Paraspeckles are known to retain within the nucleus RNAs containing inverted repeats of Alu sequences.
Paraspeckles as rhythmic nuclear mRNA anchorages responsible for circadian gene expression Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Séverine Guillen, Bénédicte Boyer, Mathias Moreno, Jean-Louis Franc & Anne-Marie François-Bellan? DOI: 10.1080/19491034.2016.1277304 Joournal Nucleus

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Future studies are needed to decipher the molecular and biological differences among these states and to determine what dynamically regulates the conformation of paraspeckles, including after cellular stimulations. The combination of live cell imaging and super-resolution microscopy in single cells may be able to address these questions.
Shedding light on paraspeckle structure by super-resolution microscopy Shi-Bin Hu, Run-Wen Yao, Ling-Ling Chen DOI: 10.1083/jcb.201609008 THe Journal of Cell Biology The Rockefeller University Press http://jcb.rupress.org/content/early/2016/09/14/jcb.201609008

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Improved imaging techniques will be needed to further delineate the detailed structure of paraspeckles and other cellular subcompartments enriched in RNAs and proteins in the future. [...] the Neat1_2 isoform is folded and binds to paraspeckle core proteins to first form paraspeckle-like units, which are bridged together by FUS proteins to form the ordered paraspeckle sphere. [...] how paraspekles sequester these AG-rich RNAs is unknown. [...] it will be of great interest to identify additional RNAs that are sequestered in paraspeckles and to dissect their exact localization.
Shedding light on paraspeckle structure by super-resolution microscopy Shi-Bin Hu, Run-Wen Yao, Ling-Ling Chen DOI: 10.1083/jcb.201609008 THe Journal of Cell Biology The Rockefeller University Press http://jcb.rupress.org/content/early/2016/09/14/jcb.201609008

Complex complexity.Dionisio_{April 2, 2017
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The mechanism involved in the circadian nuclear retention of Alu-containing egfp mRNA remains anyway to be determined. [...] post-transcriptional circadian regulation plays a major role in determining oscillations at the mRNA level. [...] circadian mRNA oscillations could be post-transcriptionally controlled through rhythmic nuclear retention by paraspeckle nuclear bodies.
Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Complex complexity.Dionisio_{March 31, 2017
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[...] circadian rhythms are driven by an internal body clock and are essential for the organism to adapt to the daily cycle of light and dark. Circadian rhythms also take place inside individual cells – for example, the amount of a given protein in a cell often rises and falls over each 24-hour period. To generate these daily fluctuations, the processes used to make proteins based on the instructions encoded within a gene must be carefully controlled.
Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Complex complexity.Dionisio_{March 31, 2017
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The circadian clock orchestrates daily rhythms in metabolism, physiology and behavior that allow organisms to anticipate regular changes in their environment, increasing their adaptation [...] [...] substantial regulation is achieved after transcription so that post-transcriptional controls are emerging as crucial modulators of circadian clocks [...] [...] post-transcriptional mechanisms including RNA splicing, polyadenylation, mRNA stability, mRNA cytoplasmic export and RNAs nuclear retention are essential layers for generation of gene expression rhythmicity [...]
Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Did somebody say "orchestrates"? Complex complexity.Dionisio_{March 31, 2017
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Paraspeckles are nuclear bodies form around the long non-coding RNA, Neat1, and RNA-binding proteins. While their role is not fully understood, they are believed to control gene expression at a post-transcriptional level by means of the nuclear retention of mRNA containing in their 3’-UTR inverted repeats of Alu sequences (IRAlu). [...] paraspeckles, thanks to their circadian expression, control circadian gene expression at a post-transcriptional level.
Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Complex complexity.Dionisio_{March 31, 2017
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[...] the knowledge concerning the presence of these modifications within the coding sequence of mRNAs is rather novel. [...] investigating the influence of these modifications on pivotal cellular processes, such as mRNA translation, will generate new research opportunities and will change our understanding of gene regulation.
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 31, 2017
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Why is the interpretation of modified codons by the ribosome not universally conserved across different species? It might even be conceivable that within one species, the translational response might vary in different tissues.
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 31, 2017
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mRNA modifications also modulate protein synthesis [...] It will be crucial to define which modified codons directly affect the ribosome as potential regulators of translation. [...] the mechanism behind this regulatory function will certainly reveal some exciting new insights in the decoding process of modified mRNA nucleotides.
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 31, 2017
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In the last decade of RNA research [...] RNA modifications have re?gained much attention. [...] the RNA modification repertoire is constantly expanding and the significance of the RNA modifications involved in several cellular aspects is currently undisputed. The emerging roles of mRNA modifications are extremely diverse [...] RNA modifications have been unveiled in unexpected places in mRNAs, thereby additionally expanding the potential functional repertoire [...] It will be an exciting and challenging future task to distinguish between meaningful epitranscriptomal marks and silent bystander modifications that simply decorate nucleic acids.
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 31, 2017
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Post-transcriptional modifications of RNA can be historically classified into two groups: edited RNA and modified RNA. The definition of edited or modified RNAs should not be taken too strictly, as these terms are often context-dependent. The modification and editing of mRNAs are essential processes that influence and regulate gene expression at the post-transcriptional level. mRNA modifications are involved in many aspects of mRNA processing, stability, folding and translation.
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 31, 2017
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More than 100 different types of RNA modifications in almost every class of non?coding and coding RNAs have been reported. Considering the effort necessary to specifically introduce modifications, the functional role of these modifications during the ‘life cycle’ of a tRNA might not yet be revealed. [...] many questions concerning the role of rRNA modifications during protein synthesis or ribosome assembly remain unanswered.
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 31, 2017
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Messenger RNA (mRNA) translation is a central process in every living organism. The regulation of translation is typically associated with the necessity of regulatory proteins and regulatory non?coding RNAs (ncRNAs). [...] equally important for the translation process are nucleotide modifications, which are present in all involved classes of RNA. Ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and mRNAs are co? or post?transcriptionally modified. [...] the precise function of many of these nucleotide derivatives remains enigmatic [...]
Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity.Dionisio_{March 30, 2017
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This is the post # 3001 in this thread. A total of over 7500 visits registered so far. Over 4500 visits were quiet -i.e. did not leave comments. In the 27 months since the OP was posted many discoveries have been published in research papers. The number of articles on the leading edge research topics keeps growing. The "Big Data" problem seems to get worse. With every new discovery the big picture seems more and more fascinating.Dionisio_{March 29, 2017
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[...] transcription and mRNA degradation machineries cross-talk to control the total mRNA concentration within a homeostatic range [...] [...] for both the ESR genes and the mitochondria-related genes, mRNA concentration correlated either positively or negatively with the GR. mRNA decay, but not transcription, was controlled by the GR in mitochondrial genes, whereas transcription, but not degradation, was modulated by the GR in ESR genes [...]
The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez; José E. Pérez-Ortín Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

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The need for novel proteins in proliferation cells is enormous (1), which means that much, and probably the majority, of the transcription effort should be dedicated to translation-related RNAs [...] [...] a primary task for transcriptional machineries is the production of these RNA molecules at a rate that is directly related to the growth rate. [...] transcription of genes encoding ribosomal components and translation-related elements is directly dependent on the GR [...]
The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez; José E. Pérez-Ortín Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

Complex complexity.Dionisio_{March 29, 2017
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The translation machinery includes the most abundant noncoding RNAs: rRNA and tRNAs. Thus the eukaryotic RNA polymerases (RNA pol) devoted to the synthesis of rRNA and tRNA (RNA pol I and III) must increase their transcription rates (TRs [...]) in parallel to the GR [...]
The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez; José E. Pérez-Ortín Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

Complex complexity.Dionisio_{March 29, 2017
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The regulation of overall mRNA turnover keeps a constant ratio between mRNA decay and the dilution of [mRNA] caused by cellular growth. This regulation minimizes the indiscriminate transmission of mRNAs from mother to daughter cells, and favors the response capacity of the latter to physiological signals and environmental changes. [...] by uncoupling mRNA synthesis from decay, cells control the mRNA abundance of those gene regulons that characterize fast and slow growth.
The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez?; José E. Pérez-Ortín? Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

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The cellular response to other environmental stresses also requires high and timely transcription of protective genes and down-regulation and later recovery of housekeeping genes, such as RP genes [...]. Our observation that cellular growth under various stresses requires Cbc1 and Cbc2 (Fig. S3), suggests that the multifunctional roles in gene expression of the mRNA cap-binding proteins are necessary to attain an adequate response to stress.
The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) – Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

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[...] a connection between recruitment of gene-specific activators to chromatin and enhanced degradation has been established [...] [...] attenuation of the stress response has been connected to nuclear protein modification and degradation of such activators as Msn2 [...] [...] dephosphorylation occurs on chromatin-bound proteins [...] [...] Cbc1 has multifunctional roles during osmotic stress, and acts as a key factor coordinating different levels of gene expression.
The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) – Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

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[...] Cbc1 connects RNA processing to all steps of transcription and also to signaling by accumulating signal-induced transcription activators at gene promoters. Further experiments should be performed to fully understand how Cbc1 mediates the accumulation of different specific activators at promoters.
The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

Complex complexity.Dionisio_{March 28, 2017
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RNAPII transcription is a complex process involving diverse, yet distinct stages, such as initiation, elongation and termination,which respond to intracellular signaling in such a dynamic manner that the mRNA being synthesized is simultaneously modified and imprinted for its subsequent life [...] Cross-talk between the factors involved in all these processes will determine the speed, intensity and length of transcription for each particular mRNA under each particular cellular condition [...] In this context, interaction between factors of different processes and the existence of factors with multifunctional roles will be necessary to achieve this complex coordination.
The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

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[...] the role of SMAR1 in memory T cell differentiation and maturation are not studied in detail and require further investigation. Since SMAR1 regulates genes that are essential for specific T cell lineage commitment, it is also important to examine whether SMAR1 plays a role in differentiation of Th9 or Th22 cells, a novel CD4+ T cells subsets. It would be interesting to study the regulation of SMAR1 in Treg cells that could be regulated by an IL-6:STAT3 or IL-2:STAT5 dependent mechanism as STAT3 and STAT5 are essential transcription factors required for Th17 and Treg differentiation, respectively. It would be also exciting to investigate whether SMAR1 play a role in the T follicular helper cell differentiation. Studies illuminating the role of lincRNAs in the regulation of SMAR1 in CD4+ T cell subtypes could also elucidate the signaling pathways and molecular mechanisms that regulate the lineage commitment of various subtypes of CD4+ T cells.
Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases Bhalchandra Mirlekar, Dipendra Gautam and Samit Chattopadhyay Front Immunol. 8: 72. doi: 10.3389/fimmu.2017.00072

Work in progress… stay tuned. Complex complexity.Dionisio_{March 28, 2017
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Various MAR-binding nuclear proteins are involved in crosstalk between genetic and epigenetic factors during differentiation of naïve T cells through chromatin changes. Studying “adaptor proteins” that bind to chromatin and define chromatin conformation provides us with cues to understand the mechanism of T cell differentiation. Further investigation into the possibilities of identifying novel molecular targets will be beneficial in modulating therapeutic interventions and immune responses.
Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases Bhalchandra Mirlekar, Dipendra Gautam and Samit Chattopadhyay Front Immunol. 8: 72. doi: 10.3389/fimmu.2017.00072

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