Hdac1 and Hdac2 positively regulate Notch1 gain‐of‐function pathogenic signaling in committed osteoblasts of male mice

Abstract

BackgroundSkeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine‐tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1‐Notch interaction has been studied in vitro and in Drosophila, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation.MethodsHere, we tested whether Hdac1/2 contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre‐activated expression of the Notch1 intracellular domain in immature osteoblasts.ResultsImportantly, selective homozygous deletions of Hdac1/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb‐Cre; TGRosaN1ICD/+; Hdac1flox/flox; Hdac2flox/flox) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4 weeks old when compared to male mice with heterozygous deletions of Hdac1/2 (Col2.3 kb‐Cre; TGRosaN1ICD/+; Hdac1flox/+; Hdac2flox/+). Osteoblast‐specific deletion of Hdac1/2 in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain‐of‐function (GOF) allele.ConclusionsThese results provide evidence that Hdac1/2 contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF‐induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch‐related GOF mutations in human patients, such as Adams‐Oliver disease, congenital heart disease, and lateral meningocele syndrome.

Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis

“…Epigenetic molecular processes dynamically modify both DNA and histone tails, influencing the spatial organization of chromatin and fine-tuning the outcome of Notch1 transcriptional response 239 . Although researchers have examined the interaction between histone deacetylase 1 (HDAC1) and Notch in vitro and in Drosophila wing development, the precise role of this interaction in mammalian skeletal development and disorders remains uncertain 240 , 241 .…”

“…Although researchers have examined the interaction between histone deacetylase 1 (HDAC1) and Notch in vitro and in Drosophila wing development, the precise role of this interaction in mammalian skeletal development and disorders remains uncertain 240 , 241 . In a murine model of osteosclerosis, HDAC1/2 has been identified as a contributor to the disease pathogenesis, which has been attributed to the conditionally cre-activated expression of the Notch1 intracellular domain in immature osteoblasts 242 . Significantly, targeted homozygous deletions of HDAC1/2 in osteoblasts result in partial alleviation of osteosclerotic phenotypes 242 .…”

“…In a murine model of osteosclerosis, HDAC1/2 has been identified as a contributor to the disease pathogenesis, which has been attributed to the conditionally cre-activated expression of the Notch1 intracellular domain in immature osteoblasts 242 . Significantly, targeted homozygous deletions of HDAC1/2 in osteoblasts result in partial alleviation of osteosclerotic phenotypes 242 . When HDAC1/2 was specifically deleted in osteoblasts of male and female mice, there was an absence of overt bone phenotypes, even in the absence of the Notch1 gain-of-function allele 242 .…”

“…Significantly, targeted homozygous deletions of HDAC1/2 in osteoblasts result in partial alleviation of osteosclerotic phenotypes 242 . When HDAC1/2 was specifically deleted in osteoblasts of male and female mice, there was an absence of overt bone phenotypes, even in the absence of the Notch1 gain-of-function allele 242 . These findings provide evidence supporting the idea that HDAC1/2 contributes to the pathogenic signaling of Notch1 in the mammalian skeleton 242 .…”