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Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points.
Epigenetics Chromatin. 2018 05 28; 11(1):22.EC

Abstract

BACKGROUND

Enhancers 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.

RESULTS

To 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.

CONCLUSIONS

Our 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.

Authors+Show Affiliations

NHGRI Hematopoiesis Section, GMBB, Bethesda, MD, USA.Pennsylvania State University, University Park, PA, USA.NHGRI Hematopoiesis Section, GMBB, Bethesda, MD, USA.Pennsylvania State University, University Park, PA, USA.NHGRI Flow Cytometry Core, Bethesda, MD, USA.No affiliation info availablePennsylvania State University, University Park, PA, USA.NHGRI Hematopoiesis Section, GMBB, Bethesda, MD, USA. tedyaz@nhgri.nih.gov.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

29807547

Citation

Heuston, Elisabeth F., et al. "Establishment of Regulatory Elements During Erythro-megakaryopoiesis Identifies Hematopoietic Lineage-commitment Points." Epigenetics & Chromatin, vol. 11, no. 1, 2018, p. 22.
Heuston EF, Keller CA, Lichtenberg J, et al. Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points. Epigenetics Chromatin. 2018;11(1):22.
Heuston, E. F., Keller, C. A., Lichtenberg, J., Giardine, B., Anderson, S. M., Hardison, R. C., & Bodine, D. M. (2018). Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points. Epigenetics & Chromatin, 11(1), 22. https://doi.org/10.1186/s13072-018-0195-z
Heuston EF, et al. Establishment of Regulatory Elements During Erythro-megakaryopoiesis Identifies Hematopoietic Lineage-commitment Points. Epigenetics Chromatin. 2018 05 28;11(1):22. PubMed PMID: 29807547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points. AU - Heuston,Elisabeth F, AU - Keller,Cheryl A, AU - Lichtenberg,Jens, AU - Giardine,Belinda, AU - Anderson,Stacie M, AU - ,, AU - Hardison,Ross C, AU - Bodine,David M, Y1 - 2018/05/28/ PY - 2018/04/14/received PY - 2018/05/21/accepted PY - 2018/5/30/entrez PY - 2018/5/29/pubmed PY - 2018/10/6/medline KW - ATAC-Seq KW - ChIP-Seq KW - Epigenetics KW - Erythropoiesis KW - Hematopoiesis KW - Lineage commitment KW - Megakaryopoiesis KW - RNA-Seq SP - 22 EP - 22 JF - Epigenetics & chromatin JO - Epigenetics Chromatin VL - 11 IS - 1 N2 - BACKGROUND: Enhancers 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. RESULTS: To 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. CONCLUSIONS: Our 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. SN - 1756-8935 UR - https://www.unboundmedicine.com/medline/citation/29807547/Establishment_of_regulatory_elements_during_erythro_megakaryopoiesis_identifies_hematopoietic_lineage_commitment_points_ L2 - https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-018-0195-z DB - PRIME DP - Unbound Medicine ER -