Enhancer repertoires are reshaped independently of early priming and heterochromatin dynamics during B cell differentiation

Abstract

A widely accepted model posits that activation of enhancers during differentiation goes through a priming step prior to lineage commitment. To investigate the chronology of enhancer repertoire establishment during hematopoiesis, we monitored epigenome dynamics during three developmental stages representing hematopoietic stem cells, B-cell progenitors and mature B-cells. We find that only a minority of enhancers primed in stem cells or progenitors become active at later stages. Furthermore, most enhancers active in differentiated cells were not primed in earlier stages. Thus, the enhancer repertoire is reshaped dynamically during B-cell differentiation and enhancer priming in early stages does not appear to be an obligate step for enhancer activation. Furthermore, our data reveal that heterochromatin and Polycomb-mediated silencing have only a minor contribution in shaping enhancer repertoires during cell differentiation. Together, our data revisit the prevalent model about epigenetic reprogramming during hematopoiesis and give insights into the formation of gene regulatory networks.

A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription

“…These “latent” enhancers have been defined as genomic regions that are devoid of TFs and enhancer-associated marks (i.e., H3K4me1 and H3K27ac), but that acquire these features upon induction of cellular signaling pathways (Ostuni et al, 2013). In accord with this view, most enhancers active in terminally differentiated blood cells are not primed in earlier stages but, instead, are established de novo during differentiation (Choukrallah et al, 2015; Luyten et al, 2014). These findings indicate that latent (or naïve) enhancers could be more general phenomena in various cell types and that they may simultaneously acquire the active enhancer marks in response to various stimuli.…”

“…The target genes with enhancers that are solely marked by H3K4me1 (lacking H3K27ac) are weakly or not expressed but can be re-activated by extracellular stimuli, indicating that H3K4me1 primes the enhancer for rapid activation (Calo and Wysocka, 2013; Heintzman et al, 2009; Rada-Iglesias et al, 2011). However, emerging evidence indicates that the vast majority of active enhancers are established de novo in the early developmental stages instead of being marked by H3K4me1 as priming enhancers (Choukrallah et al, 2015; Luyten et al, 2014). This strongly suggests that active enhancers acquire simultaneously the principal active enhancer marks (i.e., H3K27ac and H3K4me1) during gene activation, although the underlying mechanisms remain obscure.…”

Drosophilapoised enhancers are generated during tissue patterning with the help of repression

“…This may be because the primed state already resembles the poised state or because enhancer activation occurs in a more sequential fashion by multiple patterning signals. However, many poised enhancers do not become active later, and many active enhancers are not poised before activation (Wamstad et al 2012;Choukrallah et al 2015). This suggests that many mammalian enhancers may also simply be poised as a side effect of tissue patterning, as we have observed in the Drosophila DV system.…”

“…While originally described as being poised for future activation, this model is likely an oversimplification. The majority of enhancers become active without going through a poised state during prior developmental stages (Bonn et al 2012;Choukrallah et al 2015). Only a small fraction of poised enhancers are usually activated during lineage development (Rada-Iglesias et al 2011;Bonn et al 2012;Wamstad et al 2012).…”

Distinct and Shared Determinants of Cardiomyocyte Contractility in Multi-Lineage Competent Ethnically Diverse Human iPSCs

“…Bioinformatics is playing an increasing role in evaluation of iPSC lines, including development of comparative bioinformatics models that evaluate pluripotency profiles of lines developed under different platforms18 and investigation into dynamic changes within lines as cells move from pluripotency through differentiation stages192021. Also critically needed are comparative bioinformatics studies of multiple lines that are derived, differentiated and analyzed under a uniform platform by multiple comprehensive strategies.…”