Dataset Information

SATB1 Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction.

ABSTRACT: Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations, and an increased risk of developing cancer. The chromatin-binding special AT-rich sequence-binding protein-1 (SATB1) is downregulated in megakaryocyte/erythroid progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors heat shock protein 70 (HSP70) and GATA1 which accompanies MEP differentiation. SATB1 binding to specific sites surrounding the HSP70 genes promotes chromatin loops that are required for the induction of HSP70, which, in turn, promotes GATA1 induction. This demonstrates that SATB1, although gradually downregulated during myelopoiesis, maintains a biological function in early myeloid progenitors.

SUBMITTER: Wilkes MC

PROVIDER: S-EPMC10267687 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

SATB1 Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction.

Wilkes Mark C MC Chae Hee-Don HD Scanlon Vanessa V Cepika Alma-Martina AM Wentworth Ethan P EP Saxena Mallika M Eskin Ascia A Chen Zugen Z Glader Bert B Grazia Roncarolo Maria M Nelson Stanley F SF Sakamoto Kathleen M KM

Stem cells (Dayton, Ohio) 20230601 6

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations, and an increased risk of developing cancer. The chromatin-binding special AT-rich sequence-binding protein-1 (SATB1) is downregulated in megakaryocyte/erythroid progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors he ...[more]

PMID: 36987811

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Project description:BackgroundRecent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by "bulk" assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined.ResultsTo clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlate the surface immunophenotype, transcriptional profile, and differentiation potential of individual MEP cells. Highly purified, single MEP cells were analyzed using index fluorescence-activated cell sorting and parallel targeted transcriptional profiling of the same cells was performed using a specifically designed panel of genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrate that immunophenotypic MEP comprise three distinct subpopulations: "Pre-MEP," enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity; "E-MEP," strongly biased towards erythroid differentiation; and "MK-MEP," a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally defined MEP are a mixed population, as a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally primed to generate exclusively single-lineage output.ConclusionsOur study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-depth study of disorders including inherited cytopenias, myeloproliferative disorders, and erythromegakaryocytic leukemias.

Dataset Information

SATB1 Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction.

Publications

SATB1 Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction.

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