Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability

• Published in: Nature genetics Vol. 49; no. 11; pp. 1647 - 1653
• Main Authors: Rickels, Ryan, Herz, Hans-Martin, Sze, Christie C, Cao, Kaixiang, Morgan, Marc A, Collings, Clayton K, Gause, Maria, Takahashi, Yoh-hei, Wang, Lu, Rendleman, Emily J, Marshall, Stacy A, Krueger, Annika, Bartom, Elizabeth T, Piunti, Andrea, Smith, Edwin R, Abshiru, Nebiyu A, Kelleher, Neil L, Dorsett, Dale, Shilatifard, Ali
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2017; Nature Publishing Group
• Subjects: 101/58; 45; 45/15; 45/90; 631/136; 631/208/177; 631/45; 82; 82/16; 82/83; Abnormalities; Agriculture; Alleles; Amino Acid Sequence; Animal Genetics and Genomics; Animals; Baculoviridae - genetics; Bioinformatics; Biomedicine; Cancer Research; Catalysis; Cell self-renewal; Chromatin; Chromatin - chemistry; Chromatin - metabolism; Cohesin; CRISPR-Cas Systems; Developmental biology; Drosophila; Drosophila melanogaster; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Drosophila Proteins - deficiency; Drosophila Proteins - genetics; Embryo cells; Embryo, Nonmammalian; Embryos; Enhancer Elements, Genetic; Enhancers; Environmental stress; Enzymes; Gene expression; Gene Expression Regulation, Developmental; Gene Function; Gene regulation; Genetic research; Genomes; Genomics; Histone H3; Histone-Lysine N-Methyltransferase - deficiency; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - genetics; Histones - metabolism; Human Genetics; Insects; Larva - genetics; Larva - growth & development; Larva - metabolism; letter; Lysine; Mammals; Methylation; Methyltransferase; Methyltransferases; Mice; Mutation; Observations; Properties; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Regulatory sequences; Sequence Alignment; Sequence Homology, Amino Acid; Sf9 Cells; Spodoptera; Stem cell transplantation; Stem cells; Viability
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3965

Ali Shilatifard and colleagues generate
Drosophila
lines expressing catalytically deficient Trr, which normally deposits H3K4me1 at enhancers. Trr mutants undergo normal development and show minimal changes in gene expression.
Histone H3 lysine 4 monomethylation (H3K4me1) is an evolutionarily conserved feature of enhancer chromatin catalyzed by the COMPASS-like methyltransferase family, which includes Trr in
Drosophila melanogaster
and MLL3 (encoded by
KMT2C
) and MLL4 (encoded by
KMT2D
) in mammals
1
,
2
,
3
. Here we demonstrate that
Drosophila
embryos expressing catalytically deficient Trr eclose and develop to productive adulthood. Parallel experiments with a
trr
allele that augments enzyme product specificity show that conversion of H3K4me1 at enhancers to H3K4me2 and H3K4me3 is also compatible with life and results in minimal changes in gene expression. Similarly, loss of the catalytic SET domains of MLL3 and MLL4 in mouse embryonic stem cells (mESCs) does not disrupt self-renewal.
Drosophila
embryos with
trr
alleles encoding catalytic mutants manifest subtle developmental abnormalities when subjected to temperature stress or altered cohesin levels. Collectively, our findings suggest that animal development can occur in the context of Trr or mammalian COMPASS-like proteins deficient in H3K4 monomethylation activity and point to a possible role for H3K4me1 on
cis
-regulatory elements in specific settings to fine-tune transcriptional regulation in response to environmental stress.