Abstract
BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases.
Highlights
Chromatin-based transcriptional repression is mediated by macromolecular complexes containing proteins involved in chromatin writing, reading, erasing and remodeling activities
We provide evidence that the heterochromatinization factor Bromo-Adjacent-Homology domain-containing 1 (BAHD1) cooperates with mesoderm induction early response (MIER) proteins to assemble chromatin-repressive complexes that control a network of metabolic genes involved in placental and fetal growth and in cholesterol homeostasis
HET Bahd1+/mice did not show any morphological, sensory or cardiac abnormality and no change in bone density, body weight and fat, when compared to wild type (WT) littermates, and the blood chemistry and hematology parameters were within the normal range
Summary
Chromatin-based transcriptional repression is mediated by macromolecular complexes containing proteins involved in chromatin writing, reading, erasing and remodeling activities. The importance of chromatin-modifiers in development, cell differentiation and disease is well illustrated for three complexes containing the histone deacetylases HDAC1 and HDAC2: NuRD [3, 4], Sin3A [5] and CoREST [6, 7] (For reviews, see [2, 8,9,10]). We found that the Bromo-Adjacent-Homology domain-containing 1 (BAHD1) protein co-purifies with HDAC1/2, together with heterochromatin proteins HP1 and KAP1 (or TRIM28) in human embryonic kidney (HEK) 293 cells, suggesting that BAHD1 is a core component of a novel HDAC1/2-associated complex [11]. BAHD1 interacts with the Methyl-CpG-binding protein MBD1 and the H3K9 methyltransferases (KMT) SETDB1 [12] and SUV39H1 [13] and acts as a repressor, pointing to a role of BAHD1 in heterochromatin-mediated transcriptional repression [12]. Overexpression of BAHD1 in human cells induces large-scale chromatin condensation [12] and changes in the DNA methylation landscape [14]
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