Common DNA methylation dynamics in endometriod adenocarcinoma and glioblastoma suggest universal epigenomic alterations in tumorigenesis

Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. Although many cancers share these trends, little is known about the specific differences in DNA methylation changes across cancer types, particularly outside of promoters. Here, we present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. Notably, hypermethylated enhancers within EAC samples contain several transcription factor binding site clusters with enriched disease ontology terms highlighting uterine function, while hypermethylated enhancers in GBM are found to overlap active enhancer marks in adult brain. These findings suggest that loss of original cellular identity may be a shared step in tumorigenesis

AIAP: A quality control and integrative analysis package to improve ATAC-seq data analysis

Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a technique widely used to investigate genome-wide chromatin accessibility. The recently published Omni-ATAC-seq protocol substantially improves the signal/noise ratio and reduces the input cell number. High-quality data are critical to ensure accurate analysis. Several tools have been developed for assessing sequencing quality and insertion size distribution for ATAC-seq data; however, key quality control (QC) metrics have not yet been established to accurately determine the quality of ATAC-seq data. Here, we optimized the analysis strategy for ATAC-seq and defined a series of QC metrics for ATAC-seq data, including reads under peak ratio (RUPr), background (BG), promoter enrichment (ProEn), subsampling enrichment (SubEn), and other measurements. We incorporated these QC tests into our recently developed ATAC-seq Integrative Analysis Package (AIAP) to provide a complete ATAC-seq analysis system, including quality assurance, improved peak calling, and downstream differential analysis. We demonstrated a significant improvement of sensitivity (20%-60%) in both peak calling and differential analysis by processing paired-end ATAC-seq datasets using AIAP. AIAP is compiled into Docker/Singularity, and it can be executed by one command line to generate a comprehensive QC report. We used ENCODE ATAC-seq data to benchmark and generate QC recommendations, and developed qATACViewer for the user-friendly interaction with the QC report. The software, source code, and documentation of AIAP are freely available at https://github.com/Zhang-lab/ATAC-seq_QC_analysis

The transcription factor Bach2 negatively regulates murine natural killer cell maturation and function

BTB domain And CNC Homolog 2 (Bach2) is a transcription repressor that actively participates in T and B lymphocyte development, but it is unknown if Bach2 is also involved in the development of innate immune cells, such as natural killer (NK) cells. Here, we followed the expression of Bach2 during murine NK cell development, finding that it peaked in immature CD2

Evaluation of functionality for serine and threonine phosphorylation with different evolutionary ages in human and mouse

Abstract Background Rapid evolution of phosphorylation sites could provide raw materials of natural selection to fit the environment by rewiring the regulation of signal pathways. However, a large part of phosphorylation sites was suggested to be non-functional. Although the new-arising phosphorylation sites with little functional implications prevailed in fungi, the evolutionary performance of vertebrate phosphorylation sites remained elusive. Results In this study, we evaluated the functionality of human and mouse phosphorylation sites by dividing them into old, median and young age groups based on the phylogeny of vertebrates. We found the sites in the old group were more likely to be functional and involved in signaling pathways than those in the young group. A smaller proportion of sites in the young group originated from aspartate/glutamate, which could restore the ancestral functions. In addition, both the phosphorylation level and breadth was increased with the evolutionary age. Similar to cases in fungi, these results implied that the newly emerged phosphorylation sites in vertebrates were also more likely to be non-functional, especially for serine and threonine phosphorylation in disordered regions. Conclusions This study provided not only insights into the dynamics of phosphorylation evolution in vertebrates, but also new clues to identify the functional phosphorylation sites from massive noisy data

Methamphetamine-induced region-specific transcriptomic and epigenetic changes in the brain of male rats

Abstract Psychostimulant methamphetamine (METH) is neurotoxic to the brain and, therefore, its misuse leads to neurological and psychiatric disorders. The gene regulatory network (GRN) response to neurotoxic METH binge remains unclear in most brain regions. Here we examined the effects of binge METH on the GRN in the nucleus accumbens, dentate gyrus, Ammon’s horn, and subventricular zone in male rats. At 24 h after METH, ~16% of genes displayed altered expression and over a quarter of previously open chromatin regions - parts of the genome where genes are typically active - showed shifts in their accessibility. Intriguingly, most changes were unique to each area studied, and independent regulation between transcriptome and chromatin accessibility was observed. Unexpectedly, METH differentially impacted gene activity and chromatin accessibility within the dentate gyrus and Ammon’s horn. Around 70% of the affected chromatin-accessible regions in the rat brain have conserved DNA sequences in the human genome. These regions frequently act as enhancers, ramping up the activity of nearby genes, and contain mutations linked to various neurological conditions. By sketching out the gene regulatory networks associated with binge METH in specific brain regions, our study offers fresh insights into how METH can trigger profound, region-specific molecular shifts

Rapid evolution of a retro-transposable hotspot of ovine genome underlies the alteration of BMP2 expression and development of fat tails

Abstract Background Sheep have developed the ability to store fat in their tails, which is a unique way of reserving energy to survive a harsh environment. However, the mechanism underlying this adaptive trait remains largely unsolved. Results In the present study, we provide evidence for the genetic determinants of fat tails, based on whole genome sequences of 89 individual sheep. A genome-wide scan of selective sweep identified several candidate loci including a region at chromosome 13, a haplotype of which underwent rapid evolution and spread through fat-tailed populations in China and the Middle East. Sequence analysis revealed an inter-genic origin of this locus, which later became a hotspot of ruminant-specific retro-transposon named BovB. Additionally, the candidate locus was validated based on a fat- and thin-tailed cross population. The expression of an upstream gene BMP2 was differentially regulated between fat-tailed and thin-tailed individuals in tail adipose and several other tissue types. Conclusions Our findings suggest the fixation of fat tails in domestic sheep is caused by a selective sweep near a retro-transposable hotspot at chromosome 13, the diversity of which specifically affects the expression of BMP2. The present study has shed light onto the understanding of fat metabolism