Widening the clinical spectrum of Pitt-Rogers-Danks/Wolf-Hirschhorn syndromes

Mazzeu, Juliana Forte; Krepischi-Santos, Ana Cristina Victorino; Rosenberg, Carla; Lourenço, Charles Marques; Lezirovitz, Karina; Szuhai, Károly; Martelli, Lúcia Regina; Vianna‐Morgante, Angela Maria

doi:10.1590/s1415-47572007000300007

Cited by 2 publications

(2 citation statements)

References 15 publications

(21 reference statements)

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“…Mutation of H3K36 trimethyltransferase WHSC1 gene (Wolf-Hirschhorn Syndrome candidate 1, also known as NSD2) is the major cause of Wolf-Hirschhorn syndrome (WHS), characterized by developmental defects including growth delay, mental retardation, short stature, radioulnar synostosis and mesomelic limb shortness, and craniofacial abnormalities (Bergemann et al, 2005;Mazzeu et al, 2007). WHSC1 is crucial in regulating the transcriptional activation of bone-related genes, including OPN and COL1A1, through its association with RUNX2 and p300 (Lee et al, 2014).…”

Section: Histone Methyltransferases (Hmts)mentioning

confidence: 99%

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

Wan

Zhang

Yao

et al. 2021

Front. Cell Dev. Biol.

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The involvement of histone modifications in cartilage development, pathology and regeneration is becoming increasingly evident. Understanding the molecular mechanisms and consequences of histone modification enzymes in cartilage development, homeostasis and pathology provides fundamental and precise perspectives to interpret the biological behavior of chondrocytes during skeletal development and the pathogenesis of various cartilage related diseases. Candidate molecules or drugs that target histone modifying proteins have shown promising therapeutic potential in the treatment of cartilage lesions associated with joint degeneration and other chondropathies. In this review, we summarized the advances in the understanding of histone modifications in the regulation of chondrocyte fate, cartilage development and pathology, particularly the molecular writers, erasers and readers involved. In addition, we have highlighted recent studies on the use of small molecules and drugs to manipulate histone signals to regulate chondrocyte functions or treat cartilage lesions, in particular osteoarthritis (OA), and discussed their potential therapeutic benefits and limitations in preventing articular cartilage degeneration or promoting its repair or regeneration.

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“…Whsc1 (WSH candidate 1, also known as NSD2 or MMSET), the gene that encodes the histone 3 lysine 36 (H3K36) trimethyltransferase Whsc1 [5] , is deleted in every case of WHS [3] , and this deletion is necessary for the occurrence of WHS [6] . Because WHS patients show skeletal abnormalities, such as sternal hypo-ossification [7] , delayed growth, and craniofacial abnormalities [3] [8] , it has been concluded that Whsc1 is involved in bone development. However, its function in skeletal development remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Histone H3 Lysine 36 Methyltransferase Whsc1 Promotes the Association of Runx2 and p300 in the Activation of Bone-Related Genes

Lee

Nimura

et al. 2014

PLoS ONE

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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.

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Widening the clinical spectrum of Pitt-Rogers-Danks/Wolf-Hirschhorn syndromes

Cited by 2 publications

References 15 publications

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

Histone H3 Lysine 36 Methyltransferase Whsc1 Promotes the Association of Runx2 and p300 in the Activation of Bone-Related Genes

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