SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation

Abstract

SUMMARY Transcriptional and chromatin regulations mediate the liver response to nutrient availability. The role of chromatin factors involved in hormonal regulation in response to fasting is not fully understood. We have identified SETDB2, a glucocorticoid-induced putative epigenetic modifier, as a positive regulator of GR-mediated gene activation in liver. Insig2a increases during fasting to limit lipid synthesis, but the mechanism of induction is unknown. We show Insig2a induction is GR-SETDB2-dependent. SETDB2 facilitates GR chromatin enrichment and is key to glucocorticoid dependent enhancer-promoter interactions. INSIG2 is a negative regulator of SREBP and acute glucocorticoid treatment decreased active SREBP during refeeding or in livers of Ob/Ob mice; both systems of elevated SREBP-1c driven lipogenesis. Knockdown of SETDB2 or INSIG2 reversed the inhibition on active SREBPs. Overall, these studies identify a GR-SETDB2 regulatory axis of hepatic transcriptional reprogramming and identify SETDB2 as a potential target for metabolic disorders with aberrant glucocorticoid actions.

Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet‐induced insulin‐resistant mice

“…It was not known how Insig‐2a decreases during refeeding . Our data suggest that insulin‐CREBZF signaling directly inhibits the transcription of Insig‐2a during refeeding, whereas recent observations reported glucocorticoid‐SETDB2‐mediated activation of Insig‐2a during fasting . Our findings further uncover important mechanisms of the dynamic regulation of Insig‐2a during fasting to refeeding.…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…Levels of SREBP were also significantly elevated, which promote lipogenesis. The glucocorticoid‐dependent increase in Insig2a also reduced nuclear accumulation of SREBPs 66. The results from this study link glucocorticoids and GR directly to lipid metabolism by crosstalk of SETDB2 and INSIG2.…”

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression

“…Indeed, the lack of overlap between SETDB2 targets identified in E2A-PBX1 + cells and those reported in mouse bone-marrow-derived macrophages ( Schliehe et al, 2015 ), or a gastric cancer cell line ( Nishikawaji et al, 2016 ), suggests that SETDB2 downstream targets are highly dependent on biological context, but the specific mechanisms for SETDB2 recruitment to the respective chromatin sites have not been determined. Furthermore, although SETDB2 has been shown to methylate substrate H3K9me2 peptide in vitro ( Falandry et al, 2010 ), a recent report showed that SETDB2 can positively regulate specific targets independent of its H3K9me3 methyltransferase activity ( Roqueta-Rivera et al, 2016 ). However, this does not appear to apply to the maintenance of leukemias, since several of our observations support a requirement for methyltransferase activity including the following: (1) H3K9me3 methylation state and expression of the CDKN2C gene were reciprocally modulated in parallel by changes in SETDB2 expression, (2) disruption of the SET domain by CRISPR caused deleterious effects, and (3) the functional consequences of SETDB2 overexpression on leukemia cell maintenance required its SET domain ( Figure 5L ).…”