The genetics of human hematopoiesis and its disruption in disease

Bao, Erik L.; Cheng, Aaron; Sankaran, Vijay G.

doi:10.15252/emmm.201910316

Cited by 38 publications

(35 citation statements)

References 104 publications

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“…Similar systematic integration of epigenetic data in human blood cells is ongoing, which will generate equivalent resources. Such resources should provide guidance on many important problems, such as suggesting specific hypotheses for mechanisms by which genetic variants in noncoding regions can be associated with complex traits and diseases (Ulirsch et al 2016;Bao et al 2019).…”

Section: Discussionmentioning

confidence: 99%

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

et al. 2020

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Section: Discussionmentioning

confidence: 99%

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

et al. 2020

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“…Similar systematic integration of epigenetic data in human blood cells is on-going, which will generate equivalent resources. Such resources should provide guidance on many important problems, such as suggesting specific hypotheses for mechanisms by which genetic variants in non-coding regions can be associated with complex traits and diseases (Ulirsch et al 2016;Bao et al 2019).…”

mentioning

confidence: 99%

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

Xiang

Keller

Heuston

et al. 2019

Preprint

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Thousands of epigenomic datasets have been generated in the past decade, but it is difficult for researchers to effectively utilize all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established for ValIdated Systematic IntegratiON of epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By employing IDEAS as our Integrative and Discriminative Epigenome Annotation System, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of over 200,000 candidate cis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website (usevision.org) to aid research in genomics and hematopoiesis.

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“…Haematopoiesis is a process that occurs in the bone marrow (BM) where terminally mature blood cells arise from pluripotent haematopoietic stem cells (HSCs) (Bao, Cheng et al 2019). A distinctive characteristic of HSCs is self-renewal as well as multi-lineage differentiation (Weissman 2000).…”

Section: Haematopoiesismentioning

confidence: 99%

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

Mujahed

Miliara

Neddermeyer

et al. 2020

Blood

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CCTC-binding factor (CTCF) is a key regulator of gene expression through organization of the chromatin structure. Still, it is unclear how CTCF binding is perturbed in leukemia or in cancer in general. We studied CTCF binding by chromatin immunoprecipitation sequencing in cells from patients with acute myeloid leukemia (AML) and in normal bone marrow (NBM) in the context of gene expression, DNA methylation, and azacitidine exposure. CTCF binding was increased in AML compared with NBM. Aberrant CTCF binding was enriched for motifs for key myeloid transcription factors such as CEBPA, PU.1, and RUNX1. AML with TET2 mutations was characterized by a particularly strong gain of CTCF binding, highly enriched for gain in promoter regions, while AML in general was enriched for changes at enhancers. There was a strong anticorrelation between CTCF binding and DNA methylation. Gain of CTCF occupancy was associated with increased gene expression; however, the genomic location (promoter vs distal regions) and enrichment of motifs (for repressing vs activating cofactors) were decisive for the gene expression pattern. Knockdown of CTCF in K562 cells caused loss of CTCF binding and transcriptional repression of genes with changed CTCF binding in AML, as well as loss of RUNX1 binding at RUNX1/CTCF-binding sites. In addition, CTCF knockdown caused increased differentiation. Azacitidine exposure caused major changes in CTCF occupancy in AML patient cells, partly by restoring a CTCF-binding pattern similar to NBM. We conclude that AML displays an aberrant increase in CTCF occupancy that targets key genes for AML development and impacts gene expression.

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The genetics of human hematopoiesis and its disruption in disease

Cited by 38 publications

References 104 publications

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

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