scholarly journals Transcription Factor Binding in Embryonic Stem Cells Is Constrained by DNA Sequence Repeat Symmetry

2020 ◽  
Vol 118 (8) ◽  
pp. 2015-2026 ◽  
Author(s):  
Matan Goldshtein ◽  
Meir Mellul ◽  
Gai Deutch ◽  
Masahiko Imashimizu ◽  
Koh Takeuchi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Embryonic Stem Cells ◽  
Dna Sequence ◽  
Embryonic Stem ◽  
Transcription Factor Binding ◽  
Sequence Repeat ◽  
Factor Binding

scholarly journals Rewiring of transcription factor binding in differentiating human embryonic stem cells is constrained by DNA sequence repeat symmetry

2018 ◽  
Author(s):  
Matan Goldshtein ◽  
David B. Lukatsky
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Embryonic Stem Cells ◽  
Dna Binding ◽  
Dna Sequence ◽  
Histone Modifications ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Sequence Repeat ◽  
Dna Repeat

ABSTRACTWe analyze design principles of transcription factor (TF) recognition by genomic DNA in differentiating human embryonic stem cells for 36 TFs and five histone modifications in four developmental layers, using the data recently measured by Tsankov et al. This analysis reveals that DNA sequence repeat symmetry plays a central role in defining TF-DNA binding preferences across different developmental layers. In particular, we find that different TFs bind similar symmetry patterns within a given developmental layer. While the TF cluster content undergoes modifications upon transitions between different developmental layers, most TFs possess dominant preferences for similar DNA repeat symmetry types. Histone modifications also exhibit strong preferences for similar DNA repeat symmetry patterns, with the symmetry strength differentiating between different histone modifications. Overall, our findings show that despite the enormous sequence complexity of the TF-DNA binding landscape in differentiating human embryonic stem cells, this landscape can be quantitatively characterized in simple terms, using the notion of DNA sequence repeat symmetry.

scholarly journals A flexible repertoire of transcription factor binding sites and diversity threshold determines enhancer activity in embryonic stem cells

2020 ◽  
Author(s):  
Gurdeep Singh ◽  
Shanelle Mullany ◽  
Sakthi D Moorthy ◽  
Richard Zhang ◽  
Tahmid Mehdi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Embryonic Stem Cells ◽  
Binding Sites ◽  
Embryonic Stem ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Enhancer Activity ◽  
Factor Binding ◽  
Master Regulators

ABSTRACTTranscriptional enhancers are critical for development, phenotype evolution and often mutated in disease contexts; however, even in well-studied cell types, the sequence code conferring enhancer activity remains unknown. We found genomic regions with conserved binding of multiple transcription factors in mouse and human embryonic stem cells (ESCs) contain on average 12.6 conserved transcription factor binding sites (TFBS). These TFBS are a diverse repertoire of 70 different sequences representing the binding sites of both known and novel ESC regulators. Remarkably, using a diverse set of TFBS from this repertoire was sufficient to construct short synthetic enhancers with activity comparable to native enhancers. Site directed mutagenesis of conserved TFBS in endogenous enhancers or TFBS deletion from synthetic sequences revealed a requirement for more than ten different TFBS. Furthermore, specific TFBS, including the OCT4:SOX2 co-motif, are dispensable, despite co-binding the OCT4, SOX2 and NANOG master regulators of pluripotency. These findings reveal a TFBS diversity threshold overrides the need for optimized regulatory grammar and individual TFBS that bind specific master regulators.

scholarly journals The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Hamish W King ◽  
Robert J Klose
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Embryonic Stem Cells ◽  
Regulatory Element ◽  
Embryonic Stem ◽  
Cellular Reprogramming ◽  
Factor Binding ◽  
Pioneer Factor ◽  
Pioneer Factors ◽  
Element Function

Pioneer transcription factors recognise and bind their target sequences in inaccessible chromatin to establish new transcriptional networks throughout development and cellular reprogramming. During this process, pioneer factors establish an accessible chromatin state to facilitate additional transcription factor binding, yet it remains unclear how different pioneer factors achieve this. Here, we discover that the pluripotency-associated pioneer factor OCT4 binds chromatin to shape accessibility, transcription factor co-binding, and regulatory element function in mouse embryonic stem cells. Chromatin accessibility at OCT4-bound sites requires the chromatin remodeller BRG1, which is recruited to these sites by OCT4 to support additional transcription factor binding and expression of the pluripotency-associated transcriptome. Furthermore, the requirement for BRG1 in shaping OCT4 binding reflects how these target sites are used during cellular reprogramming and early mouse development. Together this reveals a distinct requirement for a chromatin remodeller in promoting the activity of the pioneer factor OCT4 and regulating the pluripotency network.

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

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.

scholarly journals DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Blood ◽  
2013 ◽  
Vol 121 (1) ◽  
pp. 178-187 ◽  
Author(s):  
Till Schoofs ◽  
Christian Rohde ◽  
Katja Hebestreit ◽  
Hans-Ulrich Klein ◽  
Stefanie Göllner ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Binding Sites ◽  
Embryonic Stem ◽  
Transcription Factor Binding ◽  
Promyelocytic Leukemia ◽  
Factor Binding ◽  
Aberrant Dna Methylation

Abstract The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia–retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor–binding sites (eg, the c-myc–binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα–binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα–mediated initiation of leukemogenesis.

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