Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.

h Transcriptional regulatory mechanisms likely contribute to the etiology of inflammatory bowel disease (IBD), as genetic variants associated with the disease are disproportionately found at regulatory elements. However, the transcription factors regulating colonic inflammation are unclear. To identify these transcription factors, we mapped epigenomic changes in the colonic epithelium upon inflammation. Epigenetic marks at transcriptional regulatory elements responded dynamically to inflammation and indicated a shift in epithelial transcriptional factor networks. Active enhancer chromatin structure at regulatory regions bound by the transcription factor hepatocyte nuclear factor 4␣ (HNF4A) was reduced during colitis. In agreement, upon an inflammatory stimulus, HNF4A was downregulated and showed a reduced ability to bind chromatin. Genetic variants that confer a predisposition to IBD map to HNF4A binding sites in the human colon cell line CaCo2, suggesting impaired HNF4A binding could underlie genetic susceptibility to IBD. Despite reduced HNF4A binding during inflammation, a temporal knockout model revealed HNF4A still actively protects against inflammatory phenotypes and promotes immune regulatory gene expression in the inflamed colonic epithelium. These findings highlight the potential for HNF4A agonists as IBD therapeutics.T he colonic epithelium is an integral component in inflammatory bowel disease (IBD) pathology, as compromised epithelial integrity permits increased interaction between the gut immune system and luminal antigens. However, the colonic epithelium is not merely a passive barrier against luminal microbes; active epithelial roles include antigen presentation, adaptive and innate immune regulation, and antimicrobial peptide production, among others (1-3). A detailed molecular understanding of the epithelium's role in IBD and how the epithelium responds to an inflammatory insult could offer therapeutic alternatives or innovations to current treatments.Transcriptional regulatory networks serve as the interface between the extracellular environment and genome regulation. Defining how the regulatory networks of the epithelium respond to inflammation could provide important insights into the role of the epithelium in IBD. Transcriptional regulatory networks can be inferred from a cell's epigenome, which is a collection of epigenomic marks, typically a histone posttranslational modification that is associated with a particular genome function. Transcriptional enhancer epigenomic marks are strong predictors of cellular identity and gene expression (4, 5). Nucleosomes containing histone 3, lysine 27 acetylation (H3K27ac) can be used to identify regions that have distal regulatory activity (transcriptional enhancers), flank chromatin-accessible transcription factor binding regions, and are predictive of active transcription in a conditionspecific manner (4, 6, 7). Changes in H3K27ac levels and DNA accessibility predict changes in transcription factor occupancy (8, 9); dynamic enhancer chromatin structur...