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.

Whsc1 links pluripotency exit with mesendoderm specification

“…Wolf-Hirschhorn syndrome patients with WHSC1 deletions often exhibit symptoms characteristic of midline defects, including craniofacial malformations and heart defects 43 . These features have been attributed to the SET-domain of the protein, since Whsc1-/-mice lacking the SET-domain largely reflect this phenotype, exhibiting aberrant craniofacial, cardiac and cartilage structures 30,44 . Our observation that ESCs lacking the SET-domain are moderately impaired in the formation of cardiac cells, while those depleted for the entire protein are strongly inhibited, support the idea that both SET-dependent and independent functions contribute to cardiac differentiation.…”

Histone Lysine Methylation and Neurodevelopmental Disorders

“…However, these mice did not show any learning deficits [ 129 ]. Although the downstream effectors of NSD2, such as RUNX2 and p300, which are known to play a role in bone development [ 130 ], have been identified, the mechanism by which NSD2 deficiency causes neurological disorders in patients with WHS is still unknown.…”

Chromatin modifiers and histone modifications in bone formation, regeneration, and therapeutic intervention for bone-related disease

“…The WHSC1 gene was originally identified due to its role in the human disease Wolf-Hirschhorn syndrome, a syndrome associated with bone abnormalities including craniofacial defects and growth abnormalities [39]. WHSC1 (also known as NSD2) encodes for a KMT that methylates H3K36 and deletion of this gene has severe effects on bone formation in mouse models through interactions with Runx2 and p300 [40]. In addition the related protein NSD1 also a H3K36-specific methyltransferase is associated with Soto syndrome, a condition characterized by macrocephaly and advanced bone ageing [41].…”