Project description:The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair, and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer.
Project description:Characterization of transcriptional landscape of HELLS in T-cell lymphoma. ChIP-seq experiments against Histone Marks and RNA-Polymerase II were performed in both control and HELLS knockdown (DOX) cells. ChIP-seq against HELLS was performed in control cells.
Project description:interactions that require remodeling proteins like the Helicase, Lymphoid-specific (HELLS). Here, we generate HELLS and de novo DNA methyltransferase 3 A and B (DNMT3A/B) knockout hu-man pluripotent stem cells and assemble telomere-to-telomere maps of whole genome bisulfite sequencing data combined with ATAC-sequencing. Disrupting HELLS induces a global loss of DNA methylation that is distinct from the de novo DNMTs, in particular over peri/centromeric satellite repeats as defined in the telomere-to-telomere genome assembly. However, HELLS is dispensable for local enhancer remodeling and the potential to differentiate into the three germ layers. Taken together, these findings further clarify the genomic targets and role of HELLS in human cells.
Project description:We used novel genetically engineered mouse models to investigate the role of HELLS during tumorigenesis. Loss of HELLS drastically decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Tumors from Rb1/p107 DKO and Rb1/p107/Hells TKO mice were analyzed for gene expression using RNA-seq.
Project description:DNA methylation is essential for genome integrity and involves multi-layered chromatin interac-tions that require remodeling proteins like the Helicase, Lymphoid-specific (HELLS). Here, we generate HELLS and de novo DNA methyltransferase 3 A and B (DNMT3A/B) knockout human pluripotent stem cells and assemble telomere-to-telomere maps of whole genome bisulfite se-quencing data combined with ATAC-sequencing. Disrupting HELLS induces a global loss of DNA methylation that is distinct from the de novo DNMTs, in particular over peri/centromeric satellite repeats as defined in the telomere-to-telomere genome assembly. However, HELLS is dispen-sable for local enhancer remodeling and the potential to differentiate into the three germ layers. Taken together, these findings further clarify the genomic targets and role of HELLS in human cells.
Project description:We used novel genetically engineered mouse models to investigate the role of HELLS during tumorigenesis. Loss of HELLS drastically decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Retinae from Rb1/p107 DKO and Rb1/p107/Hells TKO mice at postnatal day 21 were analyzed for gene expression using RNA-seq.
Project description:HELLS is a known chromatin remodeler, but its specific genomic targets have not been sufficiently described. Here, we report the generation of HELLS knockout human pluripotent cells and through telomere-to-telomere mapping of whole genome bisulfite sequencing data combined with ATAC-sequencing, we discovered a striking loss of DNA methylation over inaccessible, satellite repeats. Our study further clarifies the role of HELLS and provides insights into functional consequences through its deregulation in diseases.
Project description:We used novel genetically engineered mouse models to investigate the role of HELLS during tumorigenesis. Loss of HELLS drastically decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Retinae from Rb1/p107 DKO and Rb1/p107/Hells TKO mice at postnatal day 21 were analyzed for gene expression using ATAC-seq.
