Scaffold attachment factor B2 (SAFB2)-null mice reveal non-redundant functions of SAFB2 compared with its paralog, SAFB1

Scaffold attachment factors SAFB1 and SAFB2 are multifunctional proteins that share >70% sequence similarity. SAFB1-knockout (SAFB1−/−) mice display a high degree of lethality, severe growth retardation, and infertility in male mice. To assess the in vivo role of SAFB2, and to identify unique functions of the two paralogs, we generated SAFB2−/− mice. In stark contrast to SAFB1−/−, SAFB2−/− offspring were born at expected Mendelian ratios and did not show any obvious defects in growth or fertility. Generation of paralog-specific antibodies allowed extensive expression analysis of SAFB1 and SAFB2 in mouse tissues, showing high expression of both SAFB1 and SAFB2 in the immune system, and in hormonally controlled tissues, with especially high expression of SAFB2 in the male reproductive tract. Further analysis showed a significantly increased testis weight in SAFB2−/− mice, which was associated with an increased number of Sertoli cells. Our data suggest that this is at least in part caused by alterations in androgen-receptor function and expression upon deletion of SAFB2. Thus, despite a high degree of sequence similarity, SAFB1−/− and SAFB2−/− mice do not totally phenocopy each other. SAFB2−/− mice are viable, and do not show any major defects, and our data suggest a role for SAFB2 in the differentiation and activity of Sertoli cells that deserves further study

Histone Deacetylase 7 and FoxA1 in Estrogen-Mediated Repression of RPRM ▿ †

Activation of estrogen receptor α (ERα) results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ERα-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ERα, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ERα and represses ERα's transcriptional activity—this repression does not require HDAC7's deacetylase activity. We further show that the chromatin pioneer factor FoxA1, well known for its role in estrogen induction of genes, is recruited to the RPRM promoter, is necessary for repression of RPRM, and interacts with HDAC7. Like other FoxA1 recruitment sites, the RPRM promoter is characterized by H3K4me1/me2. Estrogen treatment causes decreases in H3K4me1/me2 and release of RNA polymerase II (Pol II) from the RPRM proximal promoter. Overall, these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM, a mechanism which could potentially be generalized to many more estrogen-repressed genes and hence be important in both normal physiology and pathological processes