Scl binds to primed enhancers in mesoderm to regulate hematopoietic and cardiac fate divergence

Abstract

Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated.

Accurate Promoter and Enhancer Identification in 127 ENCODE and Roadmap Epigenomics Cell Types and Tissues by GenoSTAN

“…EM1 contained TFs with high co-binding rate, which included TAL1, an important lineage-specific regulator for erythroid development (K562 are erythroleukemia cells) and which had been shown to interact with CEBPB, GATA1 and GATA2 at gene-distal loci [56, 58]. It also contained the enhancer-specific transcription factor P300 [59] and transcriptional activators (e.g.…”

Integrated genome-scale analysis of the transcriptional regulatory landscape in a blood stem/progenitor cell model

“…To do this, we calculated the number of promoter-interacting fragments that overlap with a given TF/histone mark, and compared this to distance-matched samples of "background noninteracting" regions (fragments for which no promoter interactions were detected as significant by the CHiCAGO pipeline) ( Figure 5A). For this analysis, we used 29 TF and 6 histone modifications, 17,18,37,47 all of which were found to be significantly enriched at promoter-interacting regions, in line with previous suggestions that TFs and their cofactors play critical roles in genomic looping. 48,49 Having established significant binding to looping regions for all TFs when considered individually, we next investigated combinatorial binding of multiple TFs.…”

The LMO2 oncogene regulates DNA replication in hematopoietic cells

“…5,6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8,9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs.…”