Cofactor-Mediated Restriction of GATA-1 Chromatin Occupancy Coordinates Lineage-Specific Gene Expression

Timothy M. Chlon; Louis C. Doré; John D. Crispino

doi:10.1016/j.molcel.2012.05.051

Cofactor-Mediated Restriction of GATA-1 Chromatin Occupancy Coordinates Lineage-Specific Gene Expression

Timothy M. Chlon, Louis C. Doré, John D. Crispino^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

GATA-1 and its cofactor FOG-1 are required for the differentiation of erythrocytes and megakaryocytes. In contrast, mast cell development requires GATA-1 and the absence of FOG-1. Through genome-wide comparison of the chromatin occupancy of GATA-1 and a naturally occurring mutant that cannot bind FOG-1 (GATA-1^V205G), we reveal that FOG-1 intricately regulates the chromatin occupancy of GATA-1. We identified GATA1-selective and GATA-1^V205G-selective binding sites and show that GATA-1, in the absence of FOG-1, occupies GATA-1^V205G-selective sites, but not GATA1-selective sites. By integrating ChIP-seq and gene expression data, we discovered that GATA-1^V205G binds and activates mast cell-specific genes via GATA-1^V205G-selective sites. We further show that exogenous expression of FOG-1 in mast cells leads to displacement of GATA-1 from mast cell-specific genes and causes their downregulation. Together these findings establish a mechanism of gene regulation whereby a non-DNA binding cofactor directly modulates the occupancy of a transcription factor to control lineage specification.

Original language	English (US)
Pages (from-to)	608-621
Number of pages	14
Journal	Molecular cell
Volume	47
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2012.05.051
State	Published - Aug 24 2012

Funding

The authors thank Ari Melnick and the Epigenomics Core at Weill Cornell Medical College. This work was supported by the Samuel Waxman Cancer Research Foundation, the Chicago Center for Systems Biology (P50 GM081892) and in part by a grant from the NCI (R01 CA101774). T.M.C. performed the experiments. T.M.C. and L.C.D. analyzed the data. J.D.C. helped design and interpret the study. T.M.C. and J.D.C. wrote the paper.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2012.05.051

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title = "Cofactor-Mediated Restriction of GATA-1 Chromatin Occupancy Coordinates Lineage-Specific Gene Expression",

abstract = "GATA-1 and its cofactor FOG-1 are required for the differentiation of erythrocytes and megakaryocytes. In contrast, mast cell development requires GATA-1 and the absence of FOG-1. Through genome-wide comparison of the chromatin occupancy of GATA-1 and a naturally occurring mutant that cannot bind FOG-1 (GATA-1V205G), we reveal that FOG-1 intricately regulates the chromatin occupancy of GATA-1. We identified GATA1-selective and GATA-1V205G-selective binding sites and show that GATA-1, in the absence of FOG-1, occupies GATA-1V205G-selective sites, but not GATA1-selective sites. By integrating ChIP-seq and gene expression data, we discovered that GATA-1V205G binds and activates mast cell-specific genes via GATA-1V205G-selective sites. We further show that exogenous expression of FOG-1 in mast cells leads to displacement of GATA-1 from mast cell-specific genes and causes their downregulation. Together these findings establish a mechanism of gene regulation whereby a non-DNA binding cofactor directly modulates the occupancy of a transcription factor to control lineage specification.",

author = "Chlon, {Timothy M.} and Dor{\'e}, {Louis C.} and Crispino, {John D.}",

note = "Funding Information: The authors thank Ari Melnick and the Epigenomics Core at Weill Cornell Medical College. This work was supported by the Samuel Waxman Cancer Research Foundation, the Chicago Center for Systems Biology (P50 GM081892) and in part by a grant from the NCI (R01 CA101774). T.M.C. performed the experiments. T.M.C. and L.C.D. analyzed the data. J.D.C. helped design and interpret the study. T.M.C. and J.D.C. wrote the paper. ",

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N2 - GATA-1 and its cofactor FOG-1 are required for the differentiation of erythrocytes and megakaryocytes. In contrast, mast cell development requires GATA-1 and the absence of FOG-1. Through genome-wide comparison of the chromatin occupancy of GATA-1 and a naturally occurring mutant that cannot bind FOG-1 (GATA-1V205G), we reveal that FOG-1 intricately regulates the chromatin occupancy of GATA-1. We identified GATA1-selective and GATA-1V205G-selective binding sites and show that GATA-1, in the absence of FOG-1, occupies GATA-1V205G-selective sites, but not GATA1-selective sites. By integrating ChIP-seq and gene expression data, we discovered that GATA-1V205G binds and activates mast cell-specific genes via GATA-1V205G-selective sites. We further show that exogenous expression of FOG-1 in mast cells leads to displacement of GATA-1 from mast cell-specific genes and causes their downregulation. Together these findings establish a mechanism of gene regulation whereby a non-DNA binding cofactor directly modulates the occupancy of a transcription factor to control lineage specification.

AB - GATA-1 and its cofactor FOG-1 are required for the differentiation of erythrocytes and megakaryocytes. In contrast, mast cell development requires GATA-1 and the absence of FOG-1. Through genome-wide comparison of the chromatin occupancy of GATA-1 and a naturally occurring mutant that cannot bind FOG-1 (GATA-1V205G), we reveal that FOG-1 intricately regulates the chromatin occupancy of GATA-1. We identified GATA1-selective and GATA-1V205G-selective binding sites and show that GATA-1, in the absence of FOG-1, occupies GATA-1V205G-selective sites, but not GATA1-selective sites. By integrating ChIP-seq and gene expression data, we discovered that GATA-1V205G binds and activates mast cell-specific genes via GATA-1V205G-selective sites. We further show that exogenous expression of FOG-1 in mast cells leads to displacement of GATA-1 from mast cell-specific genes and causes their downregulation. Together these findings establish a mechanism of gene regulation whereby a non-DNA binding cofactor directly modulates the occupancy of a transcription factor to control lineage specification.

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Cofactor-Mediated Restriction of GATA-1 Chromatin Occupancy Coordinates Lineage-Specific Gene Expression

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