Biology subjects

Larsen, E. C.

Publications and source records attributed to Larsen, E. C..

2 recordsLinked to original sources

bioRxiv2025

Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B

Polymorphisms that affect chr21 gene expression have significance for both variable severity in Down syndrome and common multifactorial conditions. Results here demonstrate "selective homolog silencing" in cells from even one individual can provide a valuable complement to large studies. In trisomic iPSC subclones that silence different chr21 homologs (via XIST-based silencing), we discovered unusually large, homolog-specific, differences in RWDD2B in iPSCs, cortical organoids and endothelial cells. RNA FISH showed RWDD2B transcription almost entirely from the H1 homolog, correlated with CpG promoter methylation differences. Polymorphisms different on H1 versus H2/H3 had strongest eQTLs in GTEx, especially in brain. Collective results indicate RWDD2B functional dosage is more frequently disconnected from copy number even compared to neighboring genes. RWDD2B function is unknown, but nearby methyl-eQTLs are implicated in osteoarthritis, and potential roles in inflammation or immune response merit consideration. This study has significance for RWDD2B regulation and demonstrates a cell-based methodology to study polymorphisms.

genetics↗

bioRxiv2021

ZNF146/OZF and ZNF507 target LINE-1 sequences

Repetitive sequences including transposable elements (TEs) and transposon-derived fragments account for nearly half of the human genome. While transposition-competent TEs must be repressed to maintain genomic stability, mutated and fragmented TEs comprising the bulk of repetitive sequences can also contribute to regulation of host gene expression and broader genome organization. Here we analyzed published ChIP-seq data sets to identify proteins broadly enriched on TEs in the human genome. We show two of the proteins identified, C2H2 zinc finger-containing proteins ZNF146 (also known as OZF) and ZNF507, are targeted to distinct sites within LINE-1 ORF2 at thousands of locations in the genome. ZNF146 binding sites are found at old and young LINE-1 elements. In contrast, ZNF507 preferentially binds at young LINE-1 sequences correlated to sequence changes in LINE-1 elements at ZNF507s binding site. To gain further insight into ZNF146 and ZNF507 function, we disrupt their expression in HEK293 cells using CRISPR/Cas9 and perform RNA sequencing, finding modest gene expression changes in cells where ZNF507 has been disrupted. We further identify a physical interaction between ZNF507 and PRMT5, suggesting ZNF507 may target arginine methylation activity to LINE-1 sequences.

cell biology↗