Enhancer-priming in ageing human bone marrow mesenchymal stromal cells contributes to immune traits

Abstract

Bone marrow mesenchymal stromal cells (BMSCs) can differentiate into adipocytes and osteoblasts, and are important regulators of the haematopoietic system. Ageing associates with an increased ratio of bone marrow adipocytes to osteoblasts and immune dysregulation. Here, we carried out an integrative multiomics analysis of ATAC-Seq, RNA-Seq and proteomics data from primary human BMSCs in a healthy cohort age between 20 - 60. We identified age-sensitive elements uniquely affecting each molecular level where transcription is mostly spared, and characterised the underlying biological pathways, revealing the interplay of age-related gene expression mechanism changes spanning multiple gene regulatory layers. Through data integration with enhancer-mediated gene regulatory network analysis, we discovered that enhancers and transcription factors influence cell differentiation potential in the ageing BMSCs. By combining our results with genome-wide association study data, we found that age-specific changes could contribute to common traits related to BMSC-derived tissues such as bone and adipose tissue, and to immune-related traits on a systemic level such as asthma. We demonstrate here that a multiomics approach is crucial for unravelling complex information, providing new insights on how ageing contributes to bone marrow- and immune-related disorders.

Global and precise identification of functional miRNA targets in mESCs by integrative analysis

“…All miRNA _KO mutants showed significantly enriched positive log2‐fold‐changes (log2FCs) as compared to a control distribution of log2FCs, with at least 60% of genes exhibiting positive log2FCs (Fig EV2E and Dataset EV4). The low detection sensitivity of the approach was in line with previous mass spectrometry studies (Tacheny et al , 2012; Ding et al , 2013; preprint: Lai et al , 2021), which also described potentially high signal variance (preprint: Lai et al , 2021).…”

Pathological LSD1 mutations repress enhancer-mediated gene regulatory networks in early differentiation

“…To dissect the link between changes in chromatin accessibility at regulatory elements and gene expression beyond simply proximity, and to connect changes in TF activity with downstream effects on target gene expression, we constructed an enhancer-mediated gene regulatory network (eGRN) based on co-variation across samples with paired RNA-seq and chromatin activity readout 15, 16 such as ATAC-seq data (Kamal et al, in preparation). We calculate correlations across samples between TF expression and ATAC-seq signal at their binding motifs (TF-to-peak correlations), and between ATAC-seq peaks and RNA expression of nearby genes (peak-to-gene correlations, Fig.…”

Impact of Environmental and Epigenetic Changes on Mesenchymal Stem Cells during Aging

“…A recent multi-omics approach on aged BMSC, including ATAC-seq, proteomics and RNAseq, identified 2152 deregulated genes [ 64 ] with BMSC aging hotspots affecting distinct chromatin subsets. Downregulated proteins consist of the cell cycle, chromatin regulation, chromatin remodelling and RNA-processing proteins, whilst upregulated genes were involved in autophagy.…”

“…The expression of adipogenic transcription factors increased, whilst the osteogenic factors decreased. Most importantly, aged-sensitive chromatin regions were enriched for single-nucleotide polymorphisms (SNPs) associated with bone density, body mass index and immune diseases [ 64 ], illustrating their relevance and how multiomic approaches can uncover genomic regions and proteins that drive age-associated diseases.…”