Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution

Abstract

We define the chromatin accessibility and transcriptional landscapes in thirteen human primary blood cell types that traverse the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, we enable “enhancer cytometry” for enumeration of pure cell types from complex populations. We identify regulators governing hematopoietic differentiation and further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility reveals unique regulatory evolution in cancer cells with progressive mutation burden. Single AML cells exhibit distinctive mixed regulome profiles of disparate developmental stages. A method to account for this regulatory heterogeneity identified cancer-specific deviations and implicated HOX factors as key regulators of pre-leukemic HSC characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.

Chromatin dynamics during the differentiation of long-term hematopoietic stem cells to multipotent progenitors

“…[8][9][10][11][12] Moreover, aberrant epigenetic marks have been identified in several hematological malignancies, consistent with clinical evidence that mutations targeting epigenetic regulators promote leukemogenesis. 44 Our study provides the first chromatin accessibility landscape maps for LT-HSCs, ST-HSCs, and MPPs.…”

“…6,7 Several studies suggest that epigenetic mechanisms play an important role in controlling HSC renewal and lineage commitment. [8][9][10][11][12] Understanding the regulatory mechanisms of HSC self-renewal and differentiation is important for both basic stem cell biology and improving the quality of stem cell transplantation in clinical settings.…”

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

“…A luciferase assay showed a marked increase of luciferase activity in cells transduced with a constitutively active STAT5 mutant and the Plek2 promoter, confirming the functional role of JAK2/STAT5 in regulating Plek2 expression ( Figure 2L). We further analyzed the Plek2 promoter region using published ATAC (assay for transposase-accessible chromatin) sequencing data (22) and revealed the high chromatin accessibility of the Plek2 locus leading to cell type-specific expression in erythroid cells compared with other cell lineages ( Figure 2, M and N), which is similar to hemoglobin genes (Supplemental Figure 1, C and D). Taken together, these data establish that Plek2 is a transcriptional target of the JAK2/STAT5 signaling pathway.…”

C/EBPα overrides epigenetic reprogramming by oncogenic transcription factors in acute myeloid leukemia

“…To test this hypothesis, we compared the expression of these genes associated with such new sites with publicly available monocyte and hematopoietic stem cell (HSC) gene expression data using GSEA. 29 Our data indeed show that increased RUNX1-ETO and RUNX1-EVI1 binding occurs close to monocyte-specific genes, which become upregulated. Conversely, after C/EBPa induction, RUNX1-ETO and RUNX1-EVI1 binding decreases at genes expressed in self-renewing HSCs, which become downregulated ( Figure 6E-F).…”