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Critical Vulnerabilities of the NuRD Complex for Fetal Hemoglobin Control

ABSTRACT: High-resolution CRISPR functional genomics reveals critical vulnerabilities of the NuRD complex for fetal hemoglobin control

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Alex Kentsis

LAB HEAD: Alex Kentsis

PROVIDER: PXD009793 | Pride | 2019-05-22

REPOSITORIES: Pride

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			Action	DRS
	170122_IgG14.raw	Raw
	170122_IgG58.raw	Raw
	170122_SN14.raw	Raw
	170122_SN58.raw	Raw
	170122_antiMTA14.raw	Raw

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Publications

Rational targeting of a NuRD subcomplex guided by comprehensive in situ mutagenesis.

Sher Falak F Hossain Mir M Seruggia Davide D Schoonenberg Vivien A C VAC Yao Qiuming Q Cifani Paolo P Dassama Laura M K LMK Cole Mitchel A MA Ren Chunyan C Vinjamur Divya S DS Macias-Trevino Claudio C Luk Kevin K McGuckin Connor C Schupp Patrick G PG Canver Matthew C MC Kurita Ryo R Nakamura Yukio Y Fujiwara Yuko Y Wolfe Scot A SA Pinello Luca L Maeda Takahiro T Kentsis Alex A Orkin Stuart H SH Bauer Daniel E DE

Nature genetics 20190628 7

Developmental silencing of fetal globins serves as both a paradigm of spatiotemporal gene regulation and an opportunity for therapeutic intervention of β-hemoglobinopathy. The nucleosome remodeling and deacetylase (NuRD) chromatin complex participates in γ-globin repression. We used pooled CRISPR screening to disrupt NuRD protein coding sequences comprehensively in human adult erythroid precursors. Essential for fetal hemoglobin (HbF) control is a non-redundant subcomplex of NuRD protein family ...[more]

PMID: 31253978

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ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression

Project description:ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression

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ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression [RNA-Seq]

Project description:Metazoan transcription factors typically regulate large numbers of genes. Here we identify via a CRISPR-Cas9 genetic screen ZNF410, a pentadactyl DNA binding protein that in human erythroid cells directly and measurably activates only one gene, the NuRD component CHD4. Specificity is conveyed by two highly evolutionarily conserved clusters of ZNF410 binding sites near the CHD4 gene with no counterparts elsewhere in the genome. Loss of ZNF410 in adult type human erythroid cell culture systems and xenotransplant settings diminishes CHD4 levels and derepresses the fetal hemoglobin genes. While previously known to be silenced by CHD4, the fetal globin genes are exposed here as among the most sensitive to reduced CHD4 levels. In vitro DNA binding assays and crystallographic studies reveal the ZNF410-DNA binding mode. ZNF410 is a remarkably selective transcriptional activator in erythroid cells whose perturbation might offer new therapeutic opportunities in the treatment of hemoglobinopathies.

2020-12-09 | GSE154961 | GEO

ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression [ChIP-Seq]

2020-12-09 | GSE154960 | GEO

ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression [ChIP-Seq]

Project description:ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression [ChIP-Seq]

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ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression [RNA-Seq]

Project description:ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression [RNA-Seq]

| PRJNA648061 | ENA

microRNA expression profiles of reticulocytes for hereditary persistence of fetal hemoglobin and β-thalssemia minor with high fetal hemoglobin.

Project description:We used microarrays to investigate differential microRNA (miRNA) expression in reticulocytes comparing reticulocytes from control individuals with normal fetal hemoglobin (HbF) level to hereditary persistence of fetal hemoglobin (HPFH) and β-thalssemia minor with high HbF, and try to find out some miRNAs associated with the mechanisms of HbF induction.

2018-01-01 | GSE93973 | GEO

The long noncoding RNA expression profiles of reticulocytes for hereditary persistence of fetal hemoglobin and β-thalssemia minor with high fetal hemoglobin.

Project description:To explore long noncoding RNA (lncRNA) expression and the biological functions of lncRNAs in fetal hemoglobin (HbF) induction, we surveyed lncRNA and mRNA expression profiles using circulating reticulocytes isolated from individuals with hereditary persistence of fetal hemoglobin (HPFH) and β-thalassaemia minor with high HbF.

2018-01-01 | GSE93971 | GEO

The LRF/ZBTB7A transcription factor is a BCL11A-independent repressor of fetal hemoglobin

Project description:Hemoglobinopathies, including sickle cell disease and _-thalassemia, are global public health concerns. Induction of fetal-type hemoglobin (HbF) is a promising means to treat these disorders; however, precisely how HbF expression is silenced in adult erythroid cells is not fully understood. Here, we show that the LRF/ZBTB7A transcription factor is a potent repressor of HbF production. LRF inactivation derepresses embryonic/fetal _-globin expression in mouse and human adult erythroid cells. We employed genome-wide analysis of the transcriptome, chromatin accessibility and LRF occupancy sites, and demonstrate that LRF occupies the _-globin loci and maintains nucleosome density necessary for _-globin silencing. LRF confers its repressive activity through a unique NuRD repressor complex independent of BCL11A. Strikingly, human erythroid lines lacking both LRF and BCL11A exhibited almost a complete switch in expression from adult- to fetal-type globin, suggesting that these two factors cumulatively represent the near entirety of _-globin repressive activity in adult erythroid cells. RNA-seq, LRF ChIP-seq and ATAC-seq assays were used to investigtae LRF binding, effect of LRF depletion on transcription and chromatin landscape in mouse and human cells.

2016-01-15 | E-GEOD-74977 | biostudies-arrayexpress

EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression [RNA-seq]

Project description:Using UNC0638 and genetic assays to inhibit EHMT1/2 and derepress fetal hemoglobin in adult hematopoietic cells.

2015-11-02 | GSE71421 | GEO

EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression [ChIP-seq]

Project description:Using UNC0638 and genetic assays to inhibit EHMT1/2 and derepress fetal hemoglobin in adult hematopoietic cells.

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