Dynamics of gene expression with positive feedback to histone modifications at bivalent domains

Experiments have shown that in embryonic stem cells, the promoters of many lineage-control genes contain “bivalent domains”, within which the nucleosomes possess both active (H3K4me3) and repressive (H3K27me3) marks. Such bivalent modifications play important roles in maintaining pluripotency in embryonic stem cells. Here, to investigate gene expression dynamics when there are regulations in bivalent histone modifications and random partition in cell divisions, we study how positive feedback to histone methylation/demethylation controls the transition dynamics of the histone modification patterns along with cell cycles. We constructed a computational model that includes dynamics of histone marks, three-stage chromatin state transitions, transcription and translation, feedbacks from protein product to enzymes to regulate the addition and removal of histone marks, and the inheritance of nucleosome state between cell cycles. The model reveals how dynamics of both nucleosome state transition and gene expression are dependent on the enzyme activities and feedback regulations. Results show that the combination of stochastic histone modification at each cell division and the deterministic feedback regulation work together to adjust the dynamics of chromatin state transition in stem cell regenerations.

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KDM6A knockout in human iPSCs alters the genome-wide histone methylation profile at active and poised enhancers, activating expression of ectoderm gene expression pathways

10.1101/2021.03.09.434633 ◽

2021 ◽

Author(s):

Shailendra S. Maurya ◽

Wei Yang ◽

Qiang Zhang ◽

Petra Erdmann-Gilmore ◽

Amelia Bystry ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Histone Modification ◽

Histone Modifications ◽

Embryonic Stem ◽

Specific Gene ◽

Regulatory Domains ◽

Genome Wide ◽

Human Ipscs ◽

Expression Pathways

AbstractKDM6A is a histone demethylase, known to remove methyl moieties at the lysine residues of histone 3-labeled (H3K27me3) poised enhancers and bivalent promoters, which regulates gene expression during the differentiation of embryonic stem cells and tissue-specific development. However, while tissue- and disease-specific analyses have been performed, little is known about the location and consequences on gene expression of these regulatory regions in human pluripotent cells. Poised enhancers and bivalent promoters function in a coordinated fashion during development, which requires timely and efficient histone modifications. Identification of KDM6A-specific gene-regulatory domains is important for understanding the developmental mechanisms controlled by these histone modifications in pluripotency. In this study, we compared genome-wide histone modification and gene expression differences in isogenic wild type and cas9-mediated KDM6A knockout human induced pluripotent stem cells (hiPSC) lines. Here, we report that the absence of KDM6A does not alter the pluripotent phenotype but does substantially alter the histone modification profile at poised and active enhancers, resulting in decreased expression of associated COMPASS complex genes KMT2C and KMT2D and subsequently increasing the expression of gene pathways involved in ectoderm differentiation.

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Modeling the relative relationship of transcription factor binding and histone modifications to gene expression levels in mouse embryonic stem cells

Nucleic Acids Research ◽

10.1093/nar/gkr752 ◽

2011 ◽

Vol 40 (2) ◽

pp. 553-568 ◽

Cited By ~ 79

Author(s):

Chao Cheng ◽

Mark Gerstein

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Transcription Factor ◽

Embryonic Stem Cells ◽

Histone Modifications ◽

Embryonic Stem ◽

Expression Levels ◽

Factor Binding ◽

Relationship Of ◽

Gene Expression Levels

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Ethanol alters cell cycle gene expression in human embryonic stem cells

Journal of Pediatric Biochemistry ◽

10.1055/s-0036-1586381 ◽

2016 ◽

Vol 01 (03) ◽

pp. 201-208 ◽

Cited By ~ 2

Author(s):

Malini Krishnamoorthy ◽

Brian Gerwe ◽

Jamie Heimburg-Molinaro ◽

Rachel Nash ◽

Jagan Arumugham ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Cell Cycle Gene ◽

Cell Cycle Gene Expression

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The Trends in Global Gene Expression in Mouse Embryonic Stem Cells During Spaceflight

Frontiers in Genetics ◽

10.3389/fgene.2019.00768 ◽

2019 ◽

Vol 10 ◽

Author(s):

Lili An ◽

Yanming Li ◽

Yingjun Fan ◽

Ning He ◽

Fanlei Ran ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Global Gene Expression ◽

Mouse Embryonic Stem Cells

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Correlation of mesodermal and pluripotency gene expression during in vitro differentiation of human embryonic stem cells

Fertility and Sterility ◽

10.1016/j.fertnstert.2013.07.487 ◽

2013 ◽

Vol 100 (3) ◽

pp. S457

Author(s):

S.-Y. Ku ◽

Y.Y. Kim ◽

H. Kim ◽

S.H. Kim ◽

Y.M. Choi ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

In Vitro Differentiation ◽

Pluripotency Gene

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3076 – FINE-TUNING GENE EXPRESSION BY CRISPRA IN MOUSE EMBRYONIC STEM CELLS FOR SPECIFIC TISSUE INDUCTION

Experimental Hematology ◽

10.1016/j.exphem.2020.09.092 ◽

2020 ◽

Vol 88 ◽

pp. S62

Author(s):

Luis Galán Palma ◽

Roshana Thambyrajah ◽

Antonella Fidanza ◽

Lesley Forrester ◽

Pablo Menéndez ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cells ◽

Fine Tuning ◽

Specific Tissue

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Positive regulators of the lineage-specific transcription factor GATA-1 in differentiating erythroid cells

Molecular and Cellular Biology ◽

10.1128/mcb.14.5.3108-3114.1994 ◽

1994 ◽

Vol 14 (5) ◽

pp. 3108-3114

Author(s):

M H Baron ◽

S M Farrington

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Transcription Factor ◽

Embryonic Stem Cells ◽

Cultured Cells ◽

Globin Gene ◽

Embryonic Stem ◽

Targeted Mutagenesis ◽

Erythroid Cell ◽

Erythroid Cells

The zinc finger transcription factor GATA-1 is a major regulator of gene expression in erythroid, megakaryocyte, and mast cell lineages. GATA-1 binds to WGATAR consensus motifs in the regulatory regions of virtually all erythroid cell-specific genes. Analyses with cultured cells and cell-free systems have provided strong evidence that GATA-1 is involved in control of globin gene expression during erythroid differentiation. Targeted mutagenesis of the GATA-1 gene in embryonic stem cells has demonstrated its requirement in normal erythroid development. Efficient rescue of the defect requires an intact GATA element in the distal promoter, suggesting autoregulatory control of GATA-1 transcription. To examine whether GATA-1 expression involves additional regulatory factors or is maintained entirely by an autoregulatory loop, we have used a transient heterokaryon system to test the ability of erythroid factors to activate the GATA-1 gene in nonerythroid nuclei. We show here that proerythroblasts and mature erythroid cells contain a diffusible activity (TAG) capable of transcriptional activation of GATA-1 and that this activity decreases during the terminal differentiation of erythroid cells. Nuclei from GATA-1- mutant embryonic stem cells can still be reprogrammed to express their globin genes in erythroid heterokaryons, indicating that de novo induction of GATA-1 is not required for globin gene activation following cell fusion.

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