Super-silencers are crucial for development and carcinogenesis in B cells

Di Huang, Hanna M. Petrykowska, Dhaneshwar Kumar, Lela Kardava, Susan Moir, Behdad Afzali, Laura Elnitski () and Ivan Ovcharenko ()
Additional contact information
Di Huang: National Institutes of Health
Hanna M. Petrykowska: National Institutes of Health
Dhaneshwar Kumar: National Institutes of Health
Lela Kardava: National Institutes of Health
Susan Moir: National Institutes of Health
Behdad Afzali: National Institutes of Health
Laura Elnitski: National Institutes of Health
Ivan Ovcharenko: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The strength of the repressive histone H3K27me3 signal varies across silencers. Focusing on regions with unusually strong signals—super-silencers—we show that B-cell super-silencers are initially linked to gene upregulation in development, with target genes highly expressed in stem cells. About 13% of B-cell super-silencers convert to super-enhancers in B-cell lymphoma; 22% of these recur in over half of patients. Genes like BCL6 and BACH2 tied to these conversions are downregulated faster by JQ1, a super-enhancer-disrupting anti-cancer agent. Super-silencers are enriched for B-cell cancer-associated variants—both somatic and germline—and translocation breakpoints, exceeding levels in other regulatory elements like CTCF binding sites. Over 80% of B-cell lymphoma t(3;14)(q27;q32) translocations fuse BCL6 super-silencers with enhancer-rich regions. Super-silencer repression depends on CpG content: CpG-rich elements block promoter–enhancer contacts; CpG-poor — inhibit looping. These findings highlight super-silencers’ key role in B-cell regulation and suggest their alteration may be a primary factor of B-cell carcinogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-63329-x

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