Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice

Dae Hwan Kim, Jennifer Chiyeon Rhee, Sujeong Yeo, Rongkun Shen, Soo-Kyung Lee, Jae Lee, Seunghee Lee

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) and its closest homolog, MLL4 (aka KMT2D), belong to two homologous transcriptional coactivator complexes, named MLL3 and MLL4 complexes, respectively. MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation are unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice. We also performed comparative genome-wide transcriptome analyses in livers of MLL3, MLL4, and MLL3;MLL4 mutant mice. These analyses revealed that MLL3 and MLL4 complexes are key epigenetic regulators of common metabolic processes and the hepatic circadian clock. Subsequent mechanistic analyses uncovered that MLL3/4 complexes function as pivotal coactivators of the circadian transcription factors (TFs), retinoid-related orphan receptor (ROR)-α and -γ, in the hepatic circadian clock. Consistent with disturbed hepatic clock gene expression in MLL4 mutant mice, we found that rhythmic fluctuation of hepatic and serum bile acid (BA) levels over the circadian cycle is abolished in MLL4 mutant mice. Our analyses also demonstrate that MLL4 primarily impinges on hepatic BA production among several regulatory pathways to control BA homeostasis. Together, our results provide strong in vivo support for important roles of both MLL3 and MLL4 in similar metabolic pathways. Conclusion: Both MLL3 and MLL4 complexes act as major epigenetic regulators of diverse metabolic processes (including circadian control of bile acid homeostasis) and as critical transcriptional coactivators of the circadian TFs, RORs.

Original languageEnglish (US)
Pages (from-to)1012-1023
Number of pages12
JournalHepatology
Volume61
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Circadian Clocks
Bile Acids and Salts
Epigenomics
Leukemia
Homeostasis
Liver
Transcription Factors
Retinoids
Methyltransferases
Gene Expression Profiling
Metabolic Networks and Pathways
Histones
Lysine

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice. / Kim, Dae Hwan; Rhee, Jennifer Chiyeon; Yeo, Sujeong; Shen, Rongkun; Lee, Soo-Kyung; Lee, Jae; Lee, Seunghee.

In: Hepatology, Vol. 61, No. 3, 01.03.2015, p. 1012-1023.

Research output: Contribution to journalArticle

Kim, Dae Hwan ; Rhee, Jennifer Chiyeon ; Yeo, Sujeong ; Shen, Rongkun ; Lee, Soo-Kyung ; Lee, Jae ; Lee, Seunghee. / Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice. In: Hepatology. 2015 ; Vol. 61, No. 3. pp. 1012-1023.
@article{1557280b8929409487ea51252ae2c11d,
title = "Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice",
abstract = "The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) and its closest homolog, MLL4 (aka KMT2D), belong to two homologous transcriptional coactivator complexes, named MLL3 and MLL4 complexes, respectively. MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation are unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice. We also performed comparative genome-wide transcriptome analyses in livers of MLL3, MLL4, and MLL3;MLL4 mutant mice. These analyses revealed that MLL3 and MLL4 complexes are key epigenetic regulators of common metabolic processes and the hepatic circadian clock. Subsequent mechanistic analyses uncovered that MLL3/4 complexes function as pivotal coactivators of the circadian transcription factors (TFs), retinoid-related orphan receptor (ROR)-α and -γ, in the hepatic circadian clock. Consistent with disturbed hepatic clock gene expression in MLL4 mutant mice, we found that rhythmic fluctuation of hepatic and serum bile acid (BA) levels over the circadian cycle is abolished in MLL4 mutant mice. Our analyses also demonstrate that MLL4 primarily impinges on hepatic BA production among several regulatory pathways to control BA homeostasis. Together, our results provide strong in vivo support for important roles of both MLL3 and MLL4 in similar metabolic pathways. Conclusion: Both MLL3 and MLL4 complexes act as major epigenetic regulators of diverse metabolic processes (including circadian control of bile acid homeostasis) and as critical transcriptional coactivators of the circadian TFs, RORs.",
author = "Kim, {Dae Hwan} and Rhee, {Jennifer Chiyeon} and Sujeong Yeo and Rongkun Shen and Soo-Kyung Lee and Jae Lee and Seunghee Lee",
year = "2015",
month = "3",
day = "1",
doi = "10.1002/hep.27578",
language = "English (US)",
volume = "61",
pages = "1012--1023",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice

AU - Kim, Dae Hwan

AU - Rhee, Jennifer Chiyeon

AU - Yeo, Sujeong

AU - Shen, Rongkun

AU - Lee, Soo-Kyung

AU - Lee, Jae

AU - Lee, Seunghee

PY - 2015/3/1

Y1 - 2015/3/1

N2 - The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) and its closest homolog, MLL4 (aka KMT2D), belong to two homologous transcriptional coactivator complexes, named MLL3 and MLL4 complexes, respectively. MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation are unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice. We also performed comparative genome-wide transcriptome analyses in livers of MLL3, MLL4, and MLL3;MLL4 mutant mice. These analyses revealed that MLL3 and MLL4 complexes are key epigenetic regulators of common metabolic processes and the hepatic circadian clock. Subsequent mechanistic analyses uncovered that MLL3/4 complexes function as pivotal coactivators of the circadian transcription factors (TFs), retinoid-related orphan receptor (ROR)-α and -γ, in the hepatic circadian clock. Consistent with disturbed hepatic clock gene expression in MLL4 mutant mice, we found that rhythmic fluctuation of hepatic and serum bile acid (BA) levels over the circadian cycle is abolished in MLL4 mutant mice. Our analyses also demonstrate that MLL4 primarily impinges on hepatic BA production among several regulatory pathways to control BA homeostasis. Together, our results provide strong in vivo support for important roles of both MLL3 and MLL4 in similar metabolic pathways. Conclusion: Both MLL3 and MLL4 complexes act as major epigenetic regulators of diverse metabolic processes (including circadian control of bile acid homeostasis) and as critical transcriptional coactivators of the circadian TFs, RORs.

AB - The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) and its closest homolog, MLL4 (aka KMT2D), belong to two homologous transcriptional coactivator complexes, named MLL3 and MLL4 complexes, respectively. MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation are unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice. We also performed comparative genome-wide transcriptome analyses in livers of MLL3, MLL4, and MLL3;MLL4 mutant mice. These analyses revealed that MLL3 and MLL4 complexes are key epigenetic regulators of common metabolic processes and the hepatic circadian clock. Subsequent mechanistic analyses uncovered that MLL3/4 complexes function as pivotal coactivators of the circadian transcription factors (TFs), retinoid-related orphan receptor (ROR)-α and -γ, in the hepatic circadian clock. Consistent with disturbed hepatic clock gene expression in MLL4 mutant mice, we found that rhythmic fluctuation of hepatic and serum bile acid (BA) levels over the circadian cycle is abolished in MLL4 mutant mice. Our analyses also demonstrate that MLL4 primarily impinges on hepatic BA production among several regulatory pathways to control BA homeostasis. Together, our results provide strong in vivo support for important roles of both MLL3 and MLL4 in similar metabolic pathways. Conclusion: Both MLL3 and MLL4 complexes act as major epigenetic regulators of diverse metabolic processes (including circadian control of bile acid homeostasis) and as critical transcriptional coactivators of the circadian TFs, RORs.

UR - http://www.scopus.com/inward/record.url?scp=84923491600&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923491600&partnerID=8YFLogxK

U2 - 10.1002/hep.27578

DO - 10.1002/hep.27578

M3 - Article

C2 - 25346535

AN - SCOPUS:84923491600

VL - 61

SP - 1012

EP - 1023

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -