SATB1 Mediates Long-Range Chromatin Interactions: A Dual Regulator of Anti-Apoptotic BCL2 and Pro-Apoptotic NOXA Genes

Abstract

Aberrant expression of special AT-rich binding protein 1 (SATB1), a global genomic organizer, has been associated with various cancers, which raises the question of how higher-order chromatin structure contributes to carcinogenesis. Disruption of apoptosis is one of the hallmarks of cancer. We previously demonstrated that SATB1 mediated specific long-range chromosomal interactions between the mbr enhancer located within 3’-UTR of the BCL2 gene and the promoter to regulate BCL2 expression during early apoptosis. In the present study, we used chromosome conformation capture (3C) assays and molecular analyses to further investigate the function of the SATB1-mediated higher-order chromatin structure in co-regulation of the anti-apoptotic BCL2 gene and the pro-apoptotic NOXA gene located 3.4Mb downstream on Chromosome 18. We demonstrated that the mbr enhancer spatially juxtaposed the promoters of BCL2 and NOXA genes through SATB1-mediated chromatin-loop in Jurkat cells. Decreased SATB1 levels switched the mbr-BCL2 loop to mbr-NOXA loop, and thus changed expression of these two genes. The SATB1-mediated dynamic switch of the chromatin loop structures was essential for the cooperative expression of the BCL2 and NOXA genes in apoptosis. Notably, the role of SATB1 was specific, since inhibition of SATB1 degradation by caspase-6 inhibitor or caspase-6-resistant SATB1 mutant reversed expression of BCL-2 and NOXA in response to apoptotic stimulation. This study reveals the critical role of SATB1-organized higher-order chromatin structure in regulating the dynamic equilibrium of apoptosis-controlling genes with antagonistic functions and suggests that aberrant SATB1 expression might contribute to cancer development by disrupting the co-regulated genes in apoptosis pathways.

Functional relevance of SATB1 in immune regulation and tumorigenesis

“…However, inhibition of SATB1 cleavage by caspase-6 inhibitor led to an increase in BCL2 expression and decrease in NOXA transcription [104]. Thus increase in SATB1 levels, may potentially disrupt the equilibrium of the apoptotic regulatory genes and may contribute to cancer development and progression.…”

“…Likewise, SATB1 induced epigenetic modification of BCL2 promoter enables binding of the transcription factor CREB to BCL2 promoter and positively regulates BCL2 expression [103]. SATB1 also regulates the expression of the proapoptotic gene NOXA via the mbr enhancer [104]. Transcription of BCL2 and NOXA genes depends on their interaction with mbr enhancer.…”

“…If the mbr enhancer binds to the BCL2 promoter, then the BCL2 gene is transcribed and NOXA is repressed and vice versa. [104]. In normal conditions, on apoptotic stimulation, SATB1 is cleaved by the protease Caspase6 reducing SATB1 induced BCL2 expression.…”

SATB1 promotes tumor metastasis and invasiveness in oral squamous cell carcinoma

“…It has been shown that over‐expression of SATB1 alters the expression of a large number of genes in a cell‐specific manner (Purbey et al , ; Tan et al , ; Oda et al , ; Yang et al , ). Initially, researches were restricted in immune cells (Kumar et al , ; Ahlfors et al , ).…”

A long-range chromatin interaction regulates SATB homeobox 1 gene expression in trophoblast stem cells

“…SATB1 and SATB2 can also form heterodimers to regulate gene expression [19,46]. It is also well-known that SATB1 can mediate long-range chromatin interactions for gene regulation [4,47,48]. Thus, ELF5…”