Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway

Abstract

Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3, we have previously described an Hp1bp3(-/-) mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length, and organ weight. In addition to their small size, microcomputed tomography analysis showed that Hp1bp3(-/-) mice present a dramatic impairment of their bone development and structure. By 3 weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3(-/-) bone marrow and splenocytes, respectively, showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to noncell autonomous systemic cues in vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of IGF-1, the IGF receptors, and the IGF-binding proteins (IGFBPs). At 3 weeks of age, Hp1bp3(-/-) mice exhibited a 60% reduction in circulating IGF-1 and a 4-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1, and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging

“…Functions of Hp1bp3 that have been identified include regulation of chromatin structure (Dutta, et al, 2014), gene expression (Garfinkel, et al, 2015b), cell cycle progression (Dutta, et al, 2014), and insulin signaling (Garfinkel, et al, 2015a), several of which were supported by our analyses. For example, positive correlates of Hp1bp3 were significantly enriched both in nuclear localization (Figure 6a) and insulin signaling (Fig 6b).…”

“…During CFM training, Hp1bp3 knock-out (KO) and wild-type (WT) mice (Garfinkel, et al, 2015a) showed no differences in baseline activity (Fig 4a) or shock reactivity (Fig 4b), and KO mice exhibited comparable acquisition of conditioned fear, indicating they successfully learned the context-shock association (Fig 4a). Nevertheless, KO mice exhibited long-term CFM deficits when tested 24 hours later (Fig 4c).…”

“…In addition to collected ‘health records’ at GeneNetwork.org, both genotype and transcriptome data for ~40 tissues and cells, including hippocampus, have been generated for many of the strains, which we combined with full-sequence genome data for both B6 and D2 to facilitate genetic mapping to identify individual genetic variants that correlate with traits of interest (Chesler, et al, 2005; Houtkooper, et al, 2013; Wang, et al, 2016). Hp1bp3 tm1a(EUCOMM)Wtsi mice (n = 6/group) were acquired from the European Conditional Mouse Mutagenesis program and are described elsewhere (Garfinkel, et al, 2015a). …”

HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing

“…Knockout of HP1BP3 in mice causes early post-natal lethality (~60% pups die within 24 hours after birth) (Garfinkel et al, 2015a; Garfinkel et al, 2015b). Homozygous Hp1bp3 −/− mice that survive to weaning are fertile and have a normal life span, but are significantly smaller than their littermates since birth (Garfinkel et al, 2015a; Garfinkel et al, 2015b). These mutant mice show proportional reduction in body weight, body length and organ weight as well as severe impairment in bone development.…”

HP1BP3 expression determines maternal behavior and offspring survival

“…Deletion of HP1BP3 in a knockout (KO) mouse model had a profound effect, and only 40% of Hp1bp3 −/− pups born to heterozygous parents survived to adulthood. Furthermore, surviving mice were proportionate dwarfs, and their reduced size was linked to altered expression of endocrine insulin like growth factor 1 (IGF‐1) pathway components (Garfinkel et al ). We now find that HP1BP3 deficient dams show impaired maternal behavior and anxiety reactions, leading to reduced litter survival.…”