Dynamics of the epigenetic landscape during erythroid differentiation after GATA1 restoration

Wu, Weisheng; Cheng, Yong; Keller, Cheryl A.; Ernst, Jason; Kumar, Swathi Ashok; Mishra, Tejaswini; Morrissey, Christapher S.; Dorman, Christine M.; Chen, Kuan-Bei; Drautz, Daniela I.; Giardine, Belinda; Shibata, Yoichiro; Song, Lingyun; Pimkin, Maxim; Crawford, Gregory E.; Furey, Terrence S.; Kellis, M; Miller, Webb; Taylor, James; Schuster, Stephan C.; Zhang, Yu; Chiaromonte, Francesca; Blobel, Gerd A.; Weiss, Mitchell J.; Hardison, Ross C.

doi:10.1101/gr.125088.111

Cited by 113 publications

(191 citation statements)

References 64 publications

Supporting

Mentioning

178

Contrasting

Order By: Relevance

“…These conserved sites included those potentially bound by the canonical regulators of erythroid differentiation GATA1, NF-E2 (represented by AP-1 sites in data analyzed), and KLF1/EKLF (represented by SP1 sites in data analyzed) (32). This is consistent with the notion that specific master transcriptional regulators of differentiation are critical for the process of erythropoiesis in both species (1,32,33).…”

Section: Global Gene Expression Changes During Erythroid Terminalsupporting

confidence: 73%

Transcriptional divergence and conservation of human and mouse erythropoiesis

Pishesha

Thiru

Shi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance Mouse models have been instrumental in advancing our understanding of blood cell production. Although many studies have suggested specific differences between human and mouse red cell production (erythropoiesis), a global study of such similarities and differences has been lacking. By computationally comparing global gene expression data from adult human and mouse erythroid precursors representing the distinct stages of maturation, we showed that, while the overall transcriptional landscape has changed, critical erythroid gene signatures and transcriptional regulators have remained conserved. Importantly, these analyses can serve as a tool to integrate data between human and mouse erythropoiesis research, explain why certain human blood diseases are not faithfully recapitulated in mouse models, and highlight hurdles in translating therapeutic findings from mice to humans.

show abstract

Section: Global Gene Expression Changes During Erythroid Terminalsupporting

confidence: 73%

Transcriptional divergence and conservation of human and mouse erythropoiesis

Pishesha

Thiru

Shi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…It is important to note that several GATA1/2 ChIP-Seq studies have recently been completed in erythroid and megakaryocytic cells Fujiwara et al, 2009;Yu et al, 2009;Tijssen et al, 2011;Wu et al, 2011;Doré et al, 2012). These studies have revealed that GATA1/2 predominantly function from enhancer elements and bind relatively few promoters.…”

Section: V205mmentioning

confidence: 99%

Combinatorial regulation of tissue specification by GATA and FOG factors

Chlon

Crispino

2012

Development

View full text Add to dashboard Cite

The development of complex organisms requires the formation of diverse cell types from common stem and progenitor cells. GATA family transcriptional regulators and their dedicated cofactors, termed Friend of GATA (FOG) proteins, control cell fate and differentiation in multiple tissue types from Drosophila to man. FOGs can both facilitate and antagonize GATA factor transcriptional regulation depending on the factor, cell, and even the specific gene target. In this review, we highlight recent studies that have elucidated mechanisms by which FOGs regulate GATA factor function and discuss how these factors use these diverse modes of gene regulation to control cell lineage specification throughout metazoans.

show abstract

“…number of multimeric complexes involving other TFs and can activate or repress target gene expression (29)(30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Significancementioning

confidence: 99%

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

Wakabayashi

Ulirsch

Ludwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.GATA1 | cis-regulatory elements | noncoding mutations | Mendelian erythroid disorders W hole-exome sequencing (WES) and targeted sequencing approaches have greatly accelerated our ability to identify causal genetic lesions in both previously implicated and novel genes underlying monogenic disorders (1, 2). In hematology, WES has been extremely useful for identifying unknown genetic etiologies for various disorders, such as those affecting red blood cell (RBC) production, including Diamond-Blackfan anemia and congenital dyserythropoietic anemia (3-5), disorders of RBC structure and function (6, 7), and disorders affecting other aspects of hematologic function (2, 8). Despite this considerable success, however, more than 50% of cases of presumed monogenic diseases are refractory to current WES approaches (9). Although resolving these remaining cases will benefit from improvements in exome capture (10), read alignment (11), and variant annotation methodologies (11), the importance of genetic variation occurring within regulatory elements (REs) outside of the traditionally investigated coding sequences in hematologic and other diseases is being increasingly appreciated (12).Whole-genome sequencing (WGS) approaches are becoming progressively more available and affordable, but separating pathogenic genetic variation from benign or unrelated mutations remains especially difficult outside of protein-coding gen...

show abstract

Dynamics of the epigenetic landscape during erythroid differentiation after GATA1 restoration

Cited by 113 publications

References 64 publications

Transcriptional divergence and conservation of human and mouse erythropoiesis

Transcriptional divergence and conservation of human and mouse erythropoiesis

Combinatorial regulation of tissue specification by GATA and FOG factors

Insight into GATA1 transcriptional activity through interrogation ofciselements disrupted in human erythroid disorders

Contact Info

Product

Resources

About