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

Ryan Rickels; Hans Martin Herz; Christie C. Sze; Kaixiang Cao; Marc A. Morgan; Clayton K. Collings; Maria Gause; Yoh Hei Takahashi; Lu Wang; Emily J. Rendleman; Stacy A. Marshall; Annika Krueger; Elizabeth T. Bartom; Andrea Piunti; Edwin R. Smith; Nebiyu A. Abshiru; Neil L. Kelleher; Dale Dorsett; Ali Shilatifard

doi:10.1038/ng.3965

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

Ryan Rickels, Hans Martin Herz, Christie C. Sze, Kaixiang Cao, Marc A. Morgan, Clayton K. Collings, Maria Gause, Yoh Hei Takahashi, Lu Wang, Emily J. Rendleman, Stacy A. Marshall, Annika Krueger, Elizabeth T. Bartom, Andrea Piunti, Edwin R. Smith, Nebiyu A. Abshiru, Neil L. Kelleher, Dale Dorsett, Ali Shilatifard^*

^*Corresponding author for this work

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

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Abstract

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. 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.

Original language	English (US)
Pages (from-to)	1647-1653
Number of pages	7
Journal	Nature Genetics
Volume	49
Issue number	11
DOIs	https://doi.org/10.1038/ng.3965
State	Published - Nov 1 2017

Funding

We thank members of the Shilatifard laboratory for their critical feedback during preparation of the manuscript and L. Shilatifard for editorial assistance. R.R. is supported by the NIH/NCI under the Ruth L. Kirschstein National Research Service Award (F31CA213928). A.P. is an EMBO postdoctoral fellow (ALTF 372-2015), and his work in the Shilatifard laboratory is supported by AIRC and Marie Curie Actions–People–COFUND. H.-M.H. is supported by the NIH (R00CA181506). E.R.S. is supported by the NIH (R50CA211428). C.C.S. is supported in part by an NIH/NCI training grant (T32CA09560). Studies on Drosophila Trr and the mammalian MLL3 and MLL4 COMPASS-like family in the Shilatifard laboratory are supported in part by a generous Outstanding Investigator Award from the National Institute of Health to A.S. (R35CA197569).

ASJC Scopus subject areas

Genetics

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Rickels, R., Herz, H. M., Sze, C. C., Cao, K., Morgan, M. A., Collings, C. K., Gause, M., Takahashi, Y. H., Wang, L., Rendleman, E. J., Marshall, S. A., Krueger, A., Bartom, E. T., Piunti, A., Smith, E. R., Abshiru, N. A., Kelleher, N. L., Dorsett, D., & Shilatifard, A. (2017). Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nature Genetics, 49(11), 1647-1653. https://doi.org/10.1038/ng.3965

@article{a075f9b1585f4dee8acda8f7c815e18a,

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

abstract = "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. 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.",

author = "Ryan Rickels and Herz, {Hans Martin} and Sze, {Christie C.} and Kaixiang Cao and Morgan, {Marc A.} and Collings, {Clayton K.} and Maria Gause and Takahashi, {Yoh Hei} and Lu Wang and Rendleman, {Emily J.} and Marshall, {Stacy A.} and Annika Krueger and Bartom, {Elizabeth T.} and Andrea Piunti and Smith, {Edwin R.} and Abshiru, {Nebiyu A.} and Kelleher, {Neil L.} and Dale Dorsett and Ali Shilatifard",

note = "Funding Information: We thank members of the Shilatifard laboratory for their critical feedback during preparation of the manuscript and L. Shilatifard for editorial assistance. R.R. is supported by the NIH/NCI under the Ruth L. Kirschstein National Research Service Award (F31CA213928). A.P. is an EMBO postdoctoral fellow (ALTF 372-2015), and his work in the Shilatifard laboratory is supported by AIRC and Marie Curie Actions–People–COFUND. H.-M.H. is supported by the NIH (R00CA181506). E.R.S. is supported by the NIH (R50CA211428). C.C.S. is supported in part by an NIH/NCI training grant (T32CA09560). Studies on Drosophila Trr and the mammalian MLL3 and MLL4 COMPASS-like family in the Shilatifard laboratory are supported in part by a generous Outstanding Investigator Award from the National Institute of Health to A.S. (R35CA197569).",

year = "2017",

month = nov,

day = "1",

doi = "10.1038/ng.3965",

language = "English (US)",

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Rickels, R, Herz, HM, Sze, CC, Cao, K, Morgan, MA, Collings, CK, Gause, M, Takahashi, YH, Wang, L, Rendleman, EJ, Marshall, SA, Krueger, A, Bartom, ET, Piunti, A, Smith, ER, Abshiru, NA, Kelleher, NL, Dorsett, D & Shilatifard, A 2017, 'Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability', Nature Genetics, vol. 49, no. 11, pp. 1647-1653. https://doi.org/10.1038/ng.3965

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T1 - Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability

AU - Rickels, Ryan

AU - Herz, Hans Martin

AU - Sze, Christie C.

AU - Cao, Kaixiang

AU - Morgan, Marc A.

AU - Collings, Clayton K.

AU - Gause, Maria

AU - Takahashi, Yoh Hei

AU - Wang, Lu

AU - Rendleman, Emily J.

AU - Marshall, Stacy A.

AU - Krueger, Annika

AU - Bartom, Elizabeth T.

AU - Piunti, Andrea

AU - Smith, Edwin R.

AU - Abshiru, Nebiyu A.

AU - Kelleher, Neil L.

AU - Dorsett, Dale

AU - Shilatifard, Ali

N1 - Funding Information: We thank members of the Shilatifard laboratory for their critical feedback during preparation of the manuscript and L. Shilatifard for editorial assistance. R.R. is supported by the NIH/NCI under the Ruth L. Kirschstein National Research Service Award (F31CA213928). A.P. is an EMBO postdoctoral fellow (ALTF 372-2015), and his work in the Shilatifard laboratory is supported by AIRC and Marie Curie Actions–People–COFUND. H.-M.H. is supported by the NIH (R00CA181506). E.R.S. is supported by the NIH (R50CA211428). C.C.S. is supported in part by an NIH/NCI training grant (T32CA09560). Studies on Drosophila Trr and the mammalian MLL3 and MLL4 COMPASS-like family in the Shilatifard laboratory are supported in part by a generous Outstanding Investigator Award from the National Institute of Health to A.S. (R35CA197569).

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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. 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.

AB - 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. 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.

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

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