Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification.
The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and epigenetic states at cis-regulatory elements. Here, we show that in addition to implementing H3K4me3 at promoters of bivalent genes, Mll2 (KMT2B)/COMPASS can also implement H3K4me3 at a subset of non-TSS regulatory elements, a subset of which shares epigenetic signatures of active enhancers. Our mechanistic studies reveal that association of Mll2's CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3. Although Mll2/COMPASS is required for H3K4me3 implementation on thousands of loci, generation of catalytically mutant MLL2/COMPASS demonstrated that H3K4me3 implemented by this enzyme was essential for expression of a subset of genes, including those functioning in the control of transcriptional programs during embryonic development. Our findings suggest that not all H3K4 trimethylations implemented by MLL2/COMPASS are functionally equivalent.
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Deqing
D
Hu
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Xin
X
Gao
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA.
Kaixiang
K
Cao
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA.
Marc A
MA
Morgan
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Gloria
G
Mas
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA.
Edwin R
ER
Smith
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA; Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, 303 E. Superior St., Chicago, IL 60611.
Andrew G
AG
Volk
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA.
Elizabeth T
ET
Bartom
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA; Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, 303 E. Superior St., Chicago, IL 60611; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA.
John D
JD
Crispino
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluis Companys 23, 08010 Barcelona, Spain.
Luciano
L
Di Croce
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, IL 60611, USA; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA. Electronic address: ash@northwestern.edu.
Ali
A
Shilatifard
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D049810:Genetic Speciation; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000072417:Protein Domains
D004268:DNA-Binding Proteins; D006657:Histones; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse
CXXC domain; Histone-Lysine N-Methyltransferase; Kmt2b; Mll2; chromatin; embryonic development; gene expression regulation; histone; mouse embryonic stem cell; primordial germ cell