Pre-configuring chromatin architecture with histone modifications guides hematopoietic stem cell formation in mouse embryos

Abstract

The gene activity underlying cell differentiation is regulated by a diverse set of transcription factors (TFs), histone modifications, chromatin structures and more. Although definitive hematopoietic stem cells (HSCs) are known to emerge via endothelial-to-hematopoietic transition (EHT), how the multi-layered epigenome is sequentially unfolded in a small portion of endothelial cells (ECs) transitioning into the hematopoietic fate remains elusive. With optimized low-input itChIP-seq and Hi-C assays, we performed multi-omics dissection of the HSC ontogeny trajectory across early arterial ECs (eAECs), hemogenic endothelial cells (HECs), pre-HSCs and long-term HSCs (LT-HSCs) in mouse embryos. Interestingly, HSC regulatory regions are already pre-configurated with active histone modifications as early as eAECs, preceding chromatin looping dynamics within topologically associating domains. Chromatin looping structures between enhancers and promoters only become gradually strengthened over time. Notably, RUNX1, a master TF for hematopoiesis, enriched at half of these loops is observed early from eAECs through pre-HSCs but its enrichment further increases in HSCs. RUNX1 and co-TFs together constitute a central, progressively intensified enhancer-promoter interactions. Thus, our study provides a framework to decipher how temporal epigenomic configurations fulfill cell lineage specification during development.

Stage-specific dynamic reorganization of genome topology shapes transcriptional neighborhoods in developing human retinal organoids

“…To quantify changes from euchromatin to heterochromatin during differentiation, we counted loci that stably switched between the A and B compartments. Consistent with previous studies on cell differentiation, 53 , 54 the vast majority of the genome resides in stable compartments across all five differentiation time points. Among the 13.3% compartments that change during differentiation, we observe more genomic loci undergo stable A-to-B switches (145.8 Mb) compared with stable B-to-A switches (83.9 Mb) ( Figure 2C ; Figure S2B ).…”

Reprogramming of 3D genome structure underlying HSPC development in zebrafish

“…The loop structure was more variable with less loops and weaker strength in fetal HSPC compared with adult HSPC. However, although murine nascent HSPC did not show impaired chromatin structure[16], our results in zebrafish nascent HSPC illustrated more relaxed chromatin organization and compromised A/B compartmentalization and TADs strength. This more disordered structure in zebrafish nascent HSPC was supported by changes in chromatin accessibility, gene expression as well as the chromatin entropy.…”

“…Recent studies have shown 3D genome rearrangement participate in hematopoietic differentiation and disease [12][13][14]. Role of chromatin conformation on HSPC development have preliminary explored in mice, which deepened our understanding of mechanism on HSPC fate determination [15,16]. However, the development of HSPC is a multi-staged complex process, whether the regulatory role of 3D genome to HSPC development is conserved among vertebrate and what factors participating in regulation of HSPC development through 3D genome needs further investigation.…”

Role of diffusion and reaction of the constituents in spreading of histone modification marks

“…Experimental evidence so far suggests that most of the DNA folding proteins (HP1, PRC, CTCF) bind at locations with specific histone modifications [72][73][74]. This implies that the spread of histone modifications, to some extent, would precede the 3D folding of chromatin.…”