Abstract
ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here, we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.
Highlights
Mutations in ARID1A have recently been identified in diverse cancer types, including ovarian, endometrial, and colorectal cancer (Kadoch et al, 2013)
Inactivating ARID1A mutations have been detected across a range of diverse cancer types (Kadoch et al, 2013), including 9.4% of colorectal carcinomas (Cancer Genome Atlas Network, 2012) and up to 60% of ovarian clear cell carcinoma cells (OCCCs) (Jones et al, 2010; Wiegand et al, 2010)
After confirming the synthetic lethal relationship between ARID1A and ARID1B in colorectal carcinoma proliferation, we uncovered the mechanistic basis underlying this phenomenon by examining chromatin accessibility across the genome
Summary
Mutations in ARID1A have recently been identified in diverse cancer types, including ovarian, endometrial, and colorectal cancer (Kadoch et al, 2013). The in vivo role of ARID proteins in chromatin remodeling at a genome-wide level has not been directly explored To study this question, we made use of isogenic wild-type and ARID1A homozygous mutant HCT116 lines. ARID1A and ARID1B are critical for the binding of AP-1 family members at enhancers, consistent with diminished nucleosome spacing around AP-1 motifs upon loss of ARID1A and ARID1B These alterations are highly correlated with changes in gene expression upon loss of one or both ARID proteins and we observe significant changes in the expression of genes encoding signaling intermediates in cell growth and adhesion, including MET. Applying similar techniques in a naturally occurring ARID1A-mutant ovarian cancer cell line, we find that knockdown of ARID1B results in loss of accessibility and active histone marks around AP-1 motifs at enhancers, suggesting a common mechanistic function for ARID proteins across cancer types. Our results demonstrate a role for ARID1A and ARID1B in maintaining chromatin accessibility and define nucleosome remodeling as a critical function underlying the tumor suppressor role of ARID1A and the synthetic lethal relationship of ARID1A and ARID1B
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
