Chromatin accessibility maps provide evidence of multilineage gene priming in hematopoietic stem cells

Eric W Martin,E Camilla Forsberg,Roman E Reggiardo,Jana Krietsch,Rebekah Sousae,Daniel H Kim

doi:10.1186/s13072-020-00377-1

Eric W Martin, E Camilla Forsberg + Show 4 more

Open Access

https://doi.org/10.1186/s13072-020-00377-1

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Journal: Epigenetics & Chromatin	Publication Date: Jan 6, 2021
Citations: 23	License type: open-access

Affiliation: University of California, Santa Cruz

Abstract

Hematopoietic stem cells (HSCs) have the capacity to differentiate into vastly different types of mature blood cells. The epigenetic mechanisms regulating the multilineage ability, or multipotency, of HSCs are not well understood. To test the hypothesis that cis-regulatory elements that control fate decisions for all lineages are primed in HSCs, we used ATAC-seq to compare chromatin accessibility of HSCs with five unipotent cell types. We observed the highest similarity in accessibility profiles between megakaryocyte progenitors and HSCs, whereas B cells had the greatest number of regions with de novo gain in accessibility during differentiation. Despite these differences, we identified cis-regulatory elements from all lineages that displayed epigenetic priming in HSCs. These findings provide new insights into the regulation of stem cell multipotency, as well as a resource to identify functional drivers of lineage fate.

Highlights

Multipotency is a key feature of hematopoietic stem cells (HSCs) and essential for their ability to produce all types of blood and immune cells in situ and upon therapeutic stem cell transplantation
Mapping of chromatin accessibility in HSCs and unipotent lineage cells identified a tight association of megakaryocyte progenitors to HSCs To determine the dynamics of genome accessibility throughout hematopoiesis, we sorted six primary hematopoietic cell types (Fig. 1b) and performed ATAC-seq of libraries with expected fragment size distributions (Additional file 1: Figure S1) [8]
We identified 70,731 peaks in HSCs, 47,363 peaks in megakaryocyte progenitors (MkPs), 38,007 in erythroid progenitors (EPs), 30,529 in granulocyte/macrophages (GMs), 70,358 in B cells, and 51,832 in T cells (Table 1)

Summary

Introduction

Multipotency is a key feature of hematopoietic stem cells (HSCs) and essential for their ability to produce all types of blood and immune cells in situ and upon therapeutic stem cell transplantation. The dynamics of chromatin accessibility in erythro-megakaryopoiesis [24] and granulocyte/macrophage development [9] have been highly informative From these studies, the bulk observations gave us insight into the dynamics of lineage commitment during hematopoiesis, while single-cell analysis revealed the heterogeneity of epigenomic states and, lineage bias in progenitors throughout hematopoiesis. The bulk observations gave us insight into the dynamics of lineage commitment during hematopoiesis, while single-cell analysis revealed the heterogeneity of epigenomic states and, lineage bias in progenitors throughout hematopoiesis Based on those studies, as well as reports of global chromatin accessibility of embryonic [3, 10, 20] and hematopoietic [11, 44]. We tested this hypothesis by performing in-depth ATAC-seq investigation of HSCs and 5 unipotent lineage cell populations representing the five main hematopoietic lineages (Fig. 1b), as defined by previously published phenotypes [4, 6]

Results

Discussion

Experimental procedures