The Road Map for Megakaryopoietic Lineage from Hematopoietic Stem/Progenitor Cells

Nishikii, Hidekazu; Naoki, Katsuhiko

doi:10.1002/sctm.16-0490

Cited by 14 publications

(10 citation statements)

References 37 publications

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“…Our data suggest that there is a large population of megakaryocyte-primed cells within the multipotent progenitor population (MPP) that shares the chromatin, enhancer/promoter, and transcriptional profiles of the MPP. It is also possible that only a subpopulation of HSC are megakaryocyte-primed, but our data suggest that the majority of MPP share transcriptional and regulatory characteristics with those of the megakaryocyte population [ 4 , 15 , 31 – 34 ].…”

Section: Discussionmentioning

confidence: 96%

Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points

Heuston

Keller

Lichtenberg

et al. 2018

Epigenetics & Chromatin

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BackgroundEnhancers and promoters are cis-acting regulatory elements associated with lineage-specific gene expression. Previous studies showed that different categories of active regulatory elements are in regions of open chromatin, and each category is associated with a specific subset of post-translationally marked histones. These regulatory elements are systematically activated and repressed to promote commitment of hematopoietic stem cells along separate differentiation paths, including the closely related erythrocyte (ERY) and megakaryocyte (MK) lineages. However, the order in which these decisions are made remains unclear.ResultsTo characterize the order of cell fate decisions during hematopoiesis, we collected primary cells from mouse bone marrow and isolated 10 hematopoietic populations to generate transcriptomes and genome-wide maps of chromatin accessibility and histone H3 acetylated at lysine 27 binding (H3K27ac). Principle component analysis of transcriptional and open chromatin profiles demonstrated that cells of the megakaryocyte lineage group closely with multipotent progenitor populations, whereas erythroid cells form a separate group distinct from other populations. Using H3K27ac and open chromatin profiles, we showed that 89% of immature MK (iMK)-specific active regulatory regions are present in the most primitive hematopoietic cells, 46% of which contain active enhancer marks. These candidate active enhancers are enriched for transcription factor binding site motifs for megakaryopoiesis-essential proteins, including ERG and ETS1. In comparison, only 64% of ERY-specific active regulatory regions are present in the most primitive hematopoietic cells, 20% of which containing active enhancer marks. These regions were not enriched for any transcription factor consensus sequences. Incorporation of genome-wide DNA methylation identified significant levels of de novo methylation in iMK, but not ERY.ConclusionsOur results demonstrate that megakaryopoietic profiles are established early in hematopoiesis and are present in the majority of the hematopoietic progenitor population. However, megakaryopoiesis does not constitute a “default” differentiation pathway, as extensive de novo DNA methylation accompanies megakaryopoietic commitment. In contrast, erythropoietic profiles are not established until a later stage of hematopoiesis, and require more dramatic changes to the transcriptional and epigenetic programs. These data provide important insights into lineage commitment and can contribute to ongoing studies related to diseases associated with differentiation defects.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0195-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 96%

Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points

Heuston

Keller

Lichtenberg

et al. 2018

Epigenetics & Chromatin

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“…Thus, CD9 could be used to capture cells with stem-like molecular program. We also considered the candidature of thrombopoietin receptor MPL, which is shared between MegE and HSCs, and previously shown to enrich for cells with MegE potential in Flt3 + cells (Nishikii, Kurita, and Chiba 2017). However, we noted that the majority of Flt3 + cells express MPL thereby limiting its efficiency as a marker (Luc et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction

Safi

Dhapola

Warsi

et al. 2020

Preprint

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word count: 150 Manuscript word count: 6952 Nr of references: 61 SUMMARY The emerging notion of hematopoietic stem-and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular fate options emerge, and at which stem-like stage lineage priming is initiated. Here we investigated single-cell chromatin accessibility of Lineage -, cKit + , Sca1 + (LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 571 transcription factor-motifs revealed a population of LSK FMS-like tyrosine kinase 3(Flt3) int CD9 high cells that concurrently display stemlike and lineage-affiliated chromatin signatures pointing to a simultaneous gain of both Lympho-Myeloid and Megakaryocyte-Erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors, display multi-lineage capacity in vitro and in vivo, but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.

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“…Typically, HSCs differentiate into myeloid progenitors and eventually mature myeloid cells ( Nishikii et al, 2017 ). Dysregulation of this process results in the development of diseases such as acute myeloid leukemia (AML), an aggressive clonal disease of abnormal HSCs, and primitive progenitors that blocks their myeloid differentiation to generate self-renewing leukemia stem cells (LSCs) ( Testa, 2011 ).…”

Section: Role Of M6a In the Differentiation Of Cscsmentioning

confidence: 99%

Regulation of N6-Methyladenosine in the Differentiation of Cancer Stem Cells and Their Fate

Liu

Chen

et al. 2020

Front. Cell Dev. Biol.

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N6-methyladenosine (m6A) is one of the most common internal RNA modifications in eukaryotes. It is a dynamic and reversible process that requires an orchestrated participation of methyltransferase, demethylase, and methylated binding protein. m6A modification can affect RNA degradation, translation, and microRNA processing. m6A plays an important role in the regulation of various processes in living organisms. In addition to being involved in normal physiological processes such as sperm development, immunity, fat differentiation, cell development, and differentiation, it is also involved in tumor progression and stem cell differentiation. Curiously enough, cancer stem cells, a rare group of cells present in malignant tumors, retain the characteristics of stem cells and play an important role in the survival, proliferation, metastasis, and recurrence of cancers. Recently, studies demonstrated that m6A participates in the self-renewal and pluripotent regulation of these stem cells. However, considering that multiple targets of m6A are involved in different physiological processes, the exact role of m6A in cancer progression remains controversial. This article focuses on the mechanism of m6A and its effects on the differentiation of cancer stem cells, to provide a basis for elucidating the tumorigenesis mechanisms and exploring new potential therapeutic approaches.

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The Road Map for Megakaryopoietic Lineage from Hematopoietic Stem/Progenitor Cells

Cited by 14 publications

References 37 publications

Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points

Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points

Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction

Regulation of N6-Methyladenosine in the Differentiation of Cancer Stem Cells and Their Fate

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