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

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.