Histoprotein modification regulates mRNA shearing to determine the fate of embryonic stem cells | Genome Biology

Journal:
Yungang †, Weiling †, Scott D. Olson, Karthik S. Prabhakara and Xiaobo Zhou
: 2018/0 9/14
Digital ID: 10.1186/s13059-018-1512-3
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Embryonic Stem Cells (ESC) have in-body culture infinite proliferation, self-renewal and multi-way differentiation. The analysis of ESC cell orientation differentiation decision mechanism is very important for developmental biology and regenerative medicine. Studies have shown that variable shearing, cell cycle control and histoprotein modification play an important role in the directional differentiation of ESC. However, the complex associations between these mechanisms and how they work together and participate in the fate of the ESC have yet to be studied., it is revealed that histone modification can participate in the regulation of ESC directional differentiation by regulating variable shearing of cell cycle-related transcription factors or path path genes.
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In this paper, the researchers used human embryonic stem cell (hESC) H1 cell lineage and four cell types induced by it to differentiate (including mid-embryonic cell ME, nourishing layer cell TBL, neuromember cell NPC and interstate stem cell MSC) to represent five cell lineages with varying degrees of differentiation, and used IMR90 as a reference cell for end-differentiated cells. The authors performed an integrated analysis of the transcription and oscic groups of these cells (Figure 1). By analyzing the transcription group, the researchers first identified thousands of variable shear events associated with hESC differentiation, and the shear patterns of these events are a good example of the degree of differentiation and tissue relationship between these different cell linees.
Previous studies at a single gene level have shown that histone modification can be involved in regulating variable shear events for transcriptional coupling, which in turn reveals that histone modification can determine not only the level of gene expression (e.g. through promoters and enhanced sub-surface modifications), but also how genes are clipped. However, it is not clear how histone modification and variable shear are associated at the genome-wide level and how they are involved in a biological process (e.g. cell differentiation). Therefore, the researchers in this paper integrated and analyzed 16 histoprotein modifications (including 9 histoprotein acetylation modifications and 7 histoprotein methylation modifications) and transcription groups of the above six cells. The researchers found that before and after hESC differentiation,
(Figure 2A), suggesting that histoprotein modification may be associated with variable shear regulation. Further correlation analysis shows that the
(Figure 2B).
the authors further analyzed the function of variable shear genes closely related to histoprotein modification in order to reveal their role in ESC targeted differentiation. The analysis showed that the variable shear gene associated with histoprotein modification was closely related to the dryness of stem cells (Figure 3A) and was mainly regulated by the transcription factors associated with cell differentiation (Figure 3B). Further functional rich analysis showed that the variable shear genes associated with histone modification were mainly involved in the G2/M stage process and DNA damage repair, while other variable shear genes were mainly related to the G1/S stage process and the Wnt path (Figure 3C). Previous studies have shown that cell cycles play a crucial role in the decision of cell fate during cell differentiation. The G1/S phase is the stage in which cells receive external stimuli to obtain differentiation instructions, while the G2/M phase is the stage at which cells execute differentiation instructions and ultimately determine cell division and their fate.
, the authors analyze and experimentally validate ENCODE/Roadmap data to
. The PBX1 protein is a homeodomain transcription factor in the TALE family. Its main functions relate to lymphocytic leukemia and a variety of cancers, regulating developmental-related gene expression, and participating in cell cycle regulation. The PBX1 gene has three transcriptional ogenosomes (RefSeq notes), PBX1a, PBX1b, and PBX1c. Among them, PBX1a and PBX1b are the main transcripts, produced by the variable shear of the 7th exon. In this paper, the researchers found that the expression of PBX1a and PBX1b was significantly positively correborated with the H3K36me36 modification strength around the 7th exon during hESC differentiation, and the correlation was further confirmed by the analysis of data on 56 cells and tissues included in ENCODE/Roadmap. PBX1a is mainly highly expressed in stem cells and can promote stem cell proliferation by regulating NANOG gene expression to activate pluripotent transcription regulatory networks (Figure 4), although it has the same DNA binding domain as PBX1a, but PBX1b is expressed highly in differentiated cells. Because PBX1b is missing the functional domain of the C end, it is speculated that it has lost the transcriptional regulation activity of PBX1a, which inhibits the activity of pbX1a in differentiated cells. To confirm this hypothesization, the authors further conducted extensive molecular biology experimental analysis of H1 cell line, MSC cells induced by H1 induction and differentiation, and two MSC cell line and IMR90 cells from patients (ChIP-PCR, MOLECULAR experiments such as RIP-PCR, western-blot, etc., confirmed changes in H3K36me3 between H1 cells and other cells, as well as changes in the binding of PSIP1 and SRSF1 around chromatin and pre-mRNA 7 exons, respectively. The above results show ,
Professor Of Texas Medical Center, Professor Dr. and Mrs. Carl V. Vartian, Director of the Center for Computing and Systems Medicine. Mainly engaged in data mining, machine learning, bio-information, systems biology, biomedical imaging, regenerative medicine, clinical and translational medical information, and surgical design and optimization. He has worked in the research and development of big data, biomedical information and imaging at Peking University, Tsinghua University, Landa, Huawei, Missouri-Colombia University, Texas A-M University, Harvard University, Cornell University, Wake Forest University, university of Texas Medical Center, etc.first
assistant professor at the University of Texas Medical Center. He received his Ph.D. in Biometrics from Harbin University of Technology in 2014 and has a Bachelor's and Master's degrees in Biology. He has worked in postdoctoral research at Wake Forest University and the University of Texas Medical Center, focusing on bio-information and computational biology. The specific research includes the field of system biology such as gene and miRNA double-layer network reconstruction, modeling and analysis, the functional genomics field of SNP, GWAS, NGS data processing and analysis, and the field of data mining such as algorithm design, statistical model construction and deep learning method development. At present, mainly engaged in high-volume sequencing data (including single-cell sequencing) of the observational and transcription group regulation research.co-founded
associate professor at the University of Texas Medical Center, usa, received master's and doctorate degrees from the University of Iowa in 1998 and 2000, respectively. He has worked in radiology and bio-information medicine related research at the University of Iowa, Wake Forest University and the University of Texas Medical Center. She has many years of research experience in radiology, oxidative stress induction and cancer biology.
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Understanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-messenger RNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear.We analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended datasets from Roadmap/ENCODE projects, we exemplify this mechanism by a cell-cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1.We reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.:(
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