Histone H3 lysine 36 methyltransferase Whsc1 promotes the association of Runx2 and p300 in the activation of bone-related genes.

Abstract

The orchestration of histone modifiers is required to establish the epigenomic status that regulates gene expression during development. Whsc1 (Wolf-Hirschhorn Syndrome candidate 1), a histone H3 lysine 36 (H3K36) trimethyltransferase, is one of the major genes associated with Wolf-Hirshhorn syndrome, which is characterized by skeletal abnormalities. However, the role of Whsc1 in skeletal development remains unclear. Here, we show that Whsc1 regulates gene expression through Runt-related transcription factor (Runx) 2, a transcription factor central to bone development, and p300, a histone acetyltransferase, to promote bone differentiation. Whsc1-/- embryos exhibited defects in ossification in the occipital bone and sternum. Whsc1 knockdown in pre-osteoblast cells perturbed histone modification patterns in bone-related genes and led to defects in bone differentiation. Whsc1 increased the association of p300 with Runx2, activating the bone-related genes Osteopontin (Opn) and Collagen type Ia (Col1a1), and Whsc1 suppressed the overactivation of these genes via H3K36 trimethylation. Our results suggest that Whsc1 fine-tunes the expression of bone-related genes by acting as a modulator in balancing H3K36 trimethylation and histone acetylation. Our results provide novel insight into the mechanisms by which this histone methyltransferase regulates gene expression.

• Authors: Yu Fei Lee, Keisuke Nimura, Wan Ning Lo, Kotaro Saga, Yasufumi Kaneda
• Journal: PloS one (PLoS One) Vol. 9 Issue 9 Pg. e106661 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25188294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Core Binding Factor Alpha 1 Subunit
• Core Binding Factor Alpha 2 Subunit
• Histones
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase
• WHSC1 protein, mouse
• p300-CBP Transcription Factors
• p300-CBP-associated factor
• Lysine

Topics

• Animals
• Bone and Bones (metabolism)
• Cell Line
• Core Binding Factor Alpha 1 Subunit (metabolism)
• Core Binding Factor Alpha 2 Subunit (metabolism)
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Histones (metabolism)
• Lysine (metabolism)
• Mice
• Mice, Knockout
• p300-CBP Transcription Factors (metabolism)