BRACHYURY directs histone acetylation to target loci during mesoderm development

Arica Beisaw; Pavel Tsaytler; Frederic Koch; Sandra U Schmitz; Maria-Theodora Melissari; Anna D Senft; Lars Wittler; Tracie Pennimpede; Karol Macura; Bernhard G Herrmann; Phillip Grote

doi:10.15252/embr.201744201

BRACHYURY directs histone acetylation to target loci during mesoderm development

EMBO Rep. 2018 Jan;19(1):118-134. doi: 10.15252/embr.201744201. Epub 2017 Nov 15.

Authors

Arica Beisaw^{1

2

3}, Pavel Tsaytler¹, Frederic Koch¹, Sandra U Schmitz¹, Maria-Theodora Melissari¹, Anna D Senft¹, Lars Wittler¹, Tracie Pennimpede¹, Karol Macura¹, Bernhard G Herrmann^{1

4}, Phillip Grote^{5

6}

Affiliations

¹ Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
² Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
³ Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁴ Institute for Medical Genetics, Charité-University Medicine Berlin Campus Benjamin Franklin, Berlin, Germany.
⁵ Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany grote@med.uni-frankfurt.de.
⁶ Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.

Abstract

T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (T^Y88A) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the T locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in T^Y88A mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal Lmo2 enhancer.

Keywords: Brachyury; Lmo2; H3K27 acetylation; T‐box factors; autoregulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Base Sequence
Cell Differentiation
Cell Lineage / genetics
Chromatin / chemistry
Chromatin / metabolism
Embryo, Mammalian
Embryonic Development / genetics*
Endothelial Cells / cytology
Endothelial Cells / metabolism
Fetal Proteins / genetics*
Fetal Proteins / metabolism
Gene Expression Regulation, Developmental
Genetic Loci
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism
Histones / genetics
Histones / metabolism*
LIM Domain Proteins / genetics
LIM Domain Proteins / metabolism
Mesoderm / cytology
Mesoderm / growth & development
Mesoderm / metabolism*
Mice
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism*
Point Mutation
Protein Binding
Signal Transduction
T-Box Domain Proteins / genetics*
T-Box Domain Proteins / metabolism
p300-CBP Transcription Factors / genetics*
p300-CBP Transcription Factors / metabolism

Substances

Adaptor Proteins, Signal Transducing
Chromatin
Fetal Proteins
Histones
LIM Domain Proteins
Lmo2 protein, mouse
T-Box Domain Proteins
p300-CBP Transcription Factors
p300-CBP-associated factor
Brachyury protein