Gene induction and repression during terminal erythropoiesis are mediated by distinct epigenetic changes

Wong, Piu; Hattangadi, Shilpa M.; Cheng, Albert W.; Frampton, Garrett M.; Young, Richard A.; Lodish, Harvey F.

doi:10.1182/blood-2011-03-341404

Cited by 111 publications

(141 citation statements)

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“…8), as has been seen for GATA1 ) and other TFs (Arvey et al 2012;Kundaje et al 2012). We have proposed that the permissive chromatin states are established no later than lineage commitment , based on the very limited changes observed in chromatin states during the substantial changes in gene expression during maturation after erythroid commitment (Wong et al 2011;Wu et al 2011). In our current study, we examined earlier stages of differentiation to infer some changes in chromatin states during lineage commitment.…”

Section: Discussionmentioning

confidence: 99%

Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large-scale reprogramming of gene expression during hematopoiesis

Morrissey

Keller

et al. 2014

Genome Res.

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We used mouse ENCODE data along with complementary data from other laboratories to study the dynamics of occupancy and the role in gene regulation of the transcription factor TAL1, a critical regulator of hematopoiesis, at multiple stages of hematopoietic differentiation. We combined ChIP-seq and RNA-seq data in six mouse cell types representing a progression from multilineage precursors to differentiated erythroblasts and megakaryocytes. We found that sites of occupancy shift dramatically during commitment to the erythroid lineage, vary further during terminal maturation, and are strongly associated with changes in gene expression. In multilineage progenitors, the likely target genes are enriched for hematopoietic growth and functions associated with the mature cells of specific daughter lineages (such as megakaryocytes). In contrast, target genes in erythroblasts are specifically enriched for red cell functions. Furthermore, shifts in TAL1 occupancy during erythroid differentiation are associated with gene repression (dissociation) and induction (cooccupancy with GATA1). Based on both enrichment for transcription factor binding site motifs and co-occupancy determined by ChIP-seq, recruitment by GATA transcription factors appears to be a stronger determinant of TAL1 binding to chromatin than the canonical E-box binding site motif. Studies of additional proteins lead to the model that TAL1 regulates expression after being directed to a distinct subset of genomic binding sites in each cell type via its association with different complexes containing master regulators such as GATA2, ERG, and RUNX1 in multilineage cells and the lineage-specific master regulator GATA1 in erythroblasts.

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Section: Discussionmentioning

confidence: 99%

Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large-scale reprogramming of gene expression during hematopoiesis

Morrissey

Keller

et al. 2014

Genome Res.

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“…54 Changes in H4K16ac and H3K79me2 levels, rather than H3K4me3 and H3K27me3, are most predictive of the direction in changes in gene expression during terminal fetal liver erythroid differentiation. 55 Because H3K4me3 is usually associated with transcriptional initiation whereas H3K79me2 is tightly correlated with transcription elongation, control of Pol II elongation could be a mechanism for regulating erythroid gene expression. This may be mediated by GATA1 or TAL1 or their associated complexes, especially because nearby regions of genes induced during terminal erythroid development are co-occupied by these factors.…”

Section: Epigenetic Changes In Chromatin During Erythroid Differentiamentioning

confidence: 99%

From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

Hattangadi

Wong

Zhang

et al. 2011

Blood

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This article reviews the regulation of production of RBCs at several levels. We focus on the regulated expansion of burstforming unit-erythroid erythroid progenitors by glucocorticoids and other factors that occur during chronic anemia, inflammation, and other conditions of stress.We also highlight the rapid production of RBCs by the coordinated regulation of terminal proliferation and differentiation of committed erythroid colony-forming unit-erythroid progenitors by external signals, such as erythropoietin and adhesion to a fibronectin matrix. We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis. (Blood. 2011;118(24): 6258-6268) IntroductionIn mammals, definitive erythropoiesis first occurs in the fetal liver with progenitor cells from the yolk sac. 1 Within the fetal liver and the adult bone marrow, hematopoietic cells are formed continuously from a small population of pluripotent stem cells that generate progenitors committed to one or a few hematopoietic lineages (Figure 1). In the erythroid lineage, the earliest committed progenitors identified ex vivo are the slowly proliferating burstforming unit-erythroid (BFU-E). Early BFU-E cells divide and further differentiate through the mature BFU-E stage into rapidly dividing colony-forming unit-erythroid (CFU-E). 2 CFU-E progenitors divide 3 to 5 times over 2 to 3 days as they differentiate and undergo many substantial changes, including a decrease in cell size, chromatin condensation, and hemoglobinization, leading up to their enucleation and expulsion of other organelles. 3 In humans, the life span of RBCs is 120 days. Under normal conditions, approximately 1% of RBCs are synthesized each day but RBC production can increase substantially during times of acute or chronic stress, such as acute trauma or hemolysis. Exquisite short-term control of erythropoiesis is regulated by the kidney-derived cytokine erythropoietin (Epo), which is induced under hypoxic conditions and stimulates the terminal proliferation and differentiation of CFU-E progenitors. 4 BFU-E cells respond to many hormones in addition to Epo, including SCF, insulin like growth factor 1 (IGF-1), glucocorticoids (GCs), and IL-3, and IL-6. In cases of chronic erythroid stress, such as hemolysis, the number of CFU-E progenitors is insufficient to produce the needed RBCs, even under high Epo levels, and the body responds by producing more of these progenitors from BFU-E. 5 It is not entirely known which cells in the fetal liver or adult bone marrow produce these and other regulatory cytokines, or how they interact to regulate the division of BFU-E cells and control their self-renewal and their ability to differentiate into more mature CFU-E progenitors.At each stage of RBC production, intracellular signal transduction proteins and transcription factors activated downstream of these hormones interact with a group of DNA-binding and other transcription factors and chromati...

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“…In support of this view, a recent genome-wide histone modification profiling study, performed in differentiating erythroid cells, suggested that the regulation of transcription elongation plays a key role in gene induction and repression processes during cellular differentiation. 37 Future investigations will reveal whether direct transcription elongation stimulation by enhancers is a general mechanism.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Transcription regulation by distal enhancers

et al. 2012

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G enome-wide chromatin profiling efforts have shown that enhancers are often located at large distances from gene promoters within the non-coding genome. Whereas enhancers can stimulate transcription initiation by communicating with promoters via chromatin looping mechanisms, we propose that enhancers may also stimulate transcription elongation by physical interactions with intronic elements. We review here recent findings derived from the study of the hematopoietic system. IntroductionThe development of multicellular organisms relies upon the capacity of stem and progenitor cells to respond to their microenvironment and differentiate upon exposure to specific stimuli. This multi-step process involves complex epigenetic changes within regulatory transcriptional networks, which contribute to the timely activation and repression of key developmental genes. Transcription of mammalian genes relies on the presence of a variety of cis-DNA regulatory sequences such as promoters and enhancers. Whereas gene promoters can be relatively easy to identify (i.e., at the 5' end of transcriptional units), locating and characterizing enhancers is far more complicated. Transgenic experiments carried out over the last few decades have taught us important lessons about transcriptional enhancers and genomic organization. Attempts to express transgenes in animals, under the control of endogenous promoter sequences, often resulted in weak

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Gene induction and repression during terminal erythropoiesis are mediated by distinct epigenetic changes

Cited by 111 publications

References 50 publications

Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large-scale reprogramming of gene expression during hematopoiesis

Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large-scale reprogramming of gene expression during hematopoiesis

From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

Transcription regulation by distal enhancers

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