The chromatin remodelling protein LSH/HELLS regulates the amount and distribution of DNA hydroxymethylation in the genome

Abstract

Ten-Eleven Translocation (TET) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) leading to a dynamic epigenetic state of DNA that can influence transcription and chromatin organization. While TET proteins interact with complexes involved in transcriptional repression and activation, the overall understanding of the molecular mechanisms involved in TET-mediated regulation of gene expression still remains limited. Here, we show that TET proteins interact with the chromatin remodelling protein lymphoid-specific helicase (LSH/HELLS) in vivo and in vitro. In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (ESCs) knock out of Lsh leads to a significant reduction of 5-hydroxymethylation amount in the DNA. Whole genome sequencing of 5hmC in wild-type versus Lsh knock-out MEFs and ESCs showed that in absence of Lsh, some regions of the genome gain 5hmC while others lose it, with mild correlation with gene expression changes. We further show that differentially hydroxymethylated regions did not completely overlap with differentially methylated regions indicating that changes in 5hmC distribution upon Lsh knock-out are not a direct consequence of 5mC decrease. Altogether, our results suggest that LSH, which interacts with TET proteins, contributes to the regulation of 5hmC levels and distribution in MEFs and ESCs.

Unaltered hepatic wound healing response in male rats with ancestral liver injury

“…Interestingly, among the 69 genes, we find a subset of genes, such as Ahr, Il17ra , Vegfa or Ski , that are reported to play a role in hepatic stellate cells (HSCs) activation and regulation of liver fibrogenesis 28 – 32 . Consistent with the enrichment for genes involved in chromatin regulation among the 1523 genes correlated with F0 treatment history, we find Hells (also known as Lsh or Smarca6 ), a member of the SNF2 DNA helicase family and important cell proliferation regulator involved in chromatin modifications and structuration 33 – 35 among the upregulated genes (Supplementary Fig. 6a ).…”

HELLS regulates transcription in T-cell lymphomas by reducing unscheduled R-loops and by facilitating RNAPII progression

“…However, none of these 20 genes belong to HDGs (Figure 2A ). Notably, significant perturbations in the H3K9me3 binding profiles were observed in HELLS-bound pericentromeric genes ( Supplementary Figure S2C ) consistent with the hypothesis that the methylase activity of HELLS is not directly involved in the regulation of gene expression ( 22 ).…”

TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy

“…TET2 expression is upregulated in patients with diabetes and enables epigenetic changes, including reduced promoter DNA methylation, through a series of oxidative reaction [ 15 , 16 ]. Demethylation of promoter DNA alters the protein-DNA interactions and leads to changes in chromatin structure, which promotes the binding of transcription machinery and leads to gene activation [ 17 , 18 ]. Finally, the abnormal expression of TET2-related genes promotes the development of diabetic complications (such as diabetic nephropathy and DR) by engaging in pathological mechanisms such as oxidative stress and neovascularization [ 19 , 20 ].…”