Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis

Jeongkyung Lee, Pradip K. Saha, Qi Heng Yang, Seunghee Lee, Yoon Park Jung, Yousin Suh, Soo Kyung Lee, Lawrence Chan, Robert G. Roeder, Jae W. Lee

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of multiple transcription factors that include the adipogenic factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα, is associated with histone H3-Lys-4-methyltransferase (H3K4MT) MLL3 or its paralogue MLL4 in a complex named ASCOM (ASC-2 complex). Indeed, ASC-2-null mouse embryonic fibroblasts (MEFs) have been demonstrated to be refractory to PPARγ-stimulated adipogenesis and fail to express the PPARγ- responsive adipogenic marker gene aP2. However, the specific roles for MLL3 and MLL4 in adipogenesis remain undefined. Here, we provide evidence that MLL3 plays crucial roles in adipogenesis. First, MLL3Δ/Δ mice expressing a H3K4MT-inactivated mutant of MLL3 have significantly less white fat. Second, MLL3Δ/Δ MEFs are mildly but consistently less responsive to inducers of adipogenesis than WT MEFs. Third, ASC-2, MLL3, and MLL4 are recruited to the PPARγ-activated aP2 gene during adipogenesis, and PPARγ is shown to interact directly with the purified ASCOM. Moreover, although H3K4 methylation of aP2 is readily induced in WT MEFs, it is not induced in ASC-2-/- MEFs and only partially induced in MLL3Δ/Δ MEFs. These results suggest that ASCOM-MLL3 and ASCOM-MLL4 likely function as crucial but redundant H3K4MT complexes for PPARγ-dependent adipogenesis.

Original languageEnglish (US)
Pages (from-to)19229-19234
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number49
DOIs
StatePublished - Dec 9 2008

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Adipogenesis
Methyltransferases
Peroxisome Proliferator-Activated Receptors
Histones
Fibroblasts
White Adipose Tissue
Methylation
Genes
Transcription Factors

Keywords

  • Activating signal cointegrator-2
  • ASCOM
  • Coactivator
  • Peroxisome proliferator-activated receptor γ
  • Transcription

ASJC Scopus subject areas

  • General

Cite this

Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. / Lee, Jeongkyung; Saha, Pradip K.; Yang, Qi Heng; Lee, Seunghee; Jung, Yoon Park; Suh, Yousin; Lee, Soo Kyung; Chan, Lawrence; Roeder, Robert G.; Lee, Jae W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 49, 09.12.2008, p. 19229-19234.

Research output: Contribution to journalArticle

Lee, Jeongkyung ; Saha, Pradip K. ; Yang, Qi Heng ; Lee, Seunghee ; Jung, Yoon Park ; Suh, Yousin ; Lee, Soo Kyung ; Chan, Lawrence ; Roeder, Robert G. ; Lee, Jae W. / Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 49. pp. 19229-19234.
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abstract = "Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of multiple transcription factors that include the adipogenic factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα, is associated with histone H3-Lys-4-methyltransferase (H3K4MT) MLL3 or its paralogue MLL4 in a complex named ASCOM (ASC-2 complex). Indeed, ASC-2-null mouse embryonic fibroblasts (MEFs) have been demonstrated to be refractory to PPARγ-stimulated adipogenesis and fail to express the PPARγ- responsive adipogenic marker gene aP2. However, the specific roles for MLL3 and MLL4 in adipogenesis remain undefined. Here, we provide evidence that MLL3 plays crucial roles in adipogenesis. First, MLL3Δ/Δ mice expressing a H3K4MT-inactivated mutant of MLL3 have significantly less white fat. Second, MLL3Δ/Δ MEFs are mildly but consistently less responsive to inducers of adipogenesis than WT MEFs. Third, ASC-2, MLL3, and MLL4 are recruited to the PPARγ-activated aP2 gene during adipogenesis, and PPARγ is shown to interact directly with the purified ASCOM. Moreover, although H3K4 methylation of aP2 is readily induced in WT MEFs, it is not induced in ASC-2-/- MEFs and only partially induced in MLL3Δ/Δ MEFs. These results suggest that ASCOM-MLL3 and ASCOM-MLL4 likely function as crucial but redundant H3K4MT complexes for PPARγ-dependent adipogenesis.",
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AU - Saha, Pradip K.

AU - Yang, Qi Heng

AU - Lee, Seunghee

AU - Jung, Yoon Park

AU - Suh, Yousin

AU - Lee, Soo Kyung

AU - Chan, Lawrence

AU - Roeder, Robert G.

AU - Lee, Jae W.

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AB - Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of multiple transcription factors that include the adipogenic factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα, is associated with histone H3-Lys-4-methyltransferase (H3K4MT) MLL3 or its paralogue MLL4 in a complex named ASCOM (ASC-2 complex). Indeed, ASC-2-null mouse embryonic fibroblasts (MEFs) have been demonstrated to be refractory to PPARγ-stimulated adipogenesis and fail to express the PPARγ- responsive adipogenic marker gene aP2. However, the specific roles for MLL3 and MLL4 in adipogenesis remain undefined. Here, we provide evidence that MLL3 plays crucial roles in adipogenesis. First, MLL3Δ/Δ mice expressing a H3K4MT-inactivated mutant of MLL3 have significantly less white fat. Second, MLL3Δ/Δ MEFs are mildly but consistently less responsive to inducers of adipogenesis than WT MEFs. Third, ASC-2, MLL3, and MLL4 are recruited to the PPARγ-activated aP2 gene during adipogenesis, and PPARγ is shown to interact directly with the purified ASCOM. Moreover, although H3K4 methylation of aP2 is readily induced in WT MEFs, it is not induced in ASC-2-/- MEFs and only partially induced in MLL3Δ/Δ MEFs. These results suggest that ASCOM-MLL3 and ASCOM-MLL4 likely function as crucial but redundant H3K4MT complexes for PPARγ-dependent adipogenesis.

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