Biology subjects

Ho, A. D.

Publications and source records attributed to Ho, A. D..

4 recordsLinked to original sources

bioRxiv2023

Cell type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells

The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single cell genomes from 19 human donors of increasing age, revealing a heterogeneous mSV landscape in hematopoietic stem and progenitor cells (HSPCs). While mSV clonal expansions are confined to individuals over 60, de novo mSV formation occurs consistently across age, frequently leading to megabase-scale segmental aneuploidies. Cells harboring subclonal mosaicism show evidence for increased mSV formation. To enable high-resolution cell-typing of each Strand-seq library, we generated single-cell MNase-seq reference datasets for eight distinct HSPCs. Subclonal mSVs frequently exhibit enrichment in myeloid progenitors, and single-cell multiomic analysis suggests that these mSVs result in recurrent dysregulation of pathways related to proliferation and metabolism, including Ras signaling and lipid metabolism. The comprehensive mSV landscape identified in this study implicates mSVs in cell type-specific molecular phenotypes, establishing a foundation for deciphering links between mSVs, aging, and disease risk.

genomics↗

bioRxiv2021

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

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.

systems biology↗

bioRxiv2018

DNA methylation patterns of replicative senescence are strand-specific and reflect changes in chromatin conformation

Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes at specific sites in the genome. These changes might be due to an directly regulated epigenetic process, or to gradual deregulation of the epigenetic state, which is often referred to as "epigenetic drift". We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types. During reprogramming into induced pluripotent stem cells (iPSCs) particularly the culture-associated hypomethylation is reversed simultaneously with age-associated and pluripotency-associated DNAm changes. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpolulations of MSCs at later passages. Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no preferential interaction with other genomic regions that also harbor culture-associated DNAm changes. Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF. Taken together, our results indicate that DNAm changes during culture-expansion resembles epigenetic drift, which seems to occur in relation to chromatin conformation.

genomics↗

bioRxiv2017

Cytokine response of acute myeloid leukemia cells has impact on patient prognosis: Insights from mathematical modeling

Acute myeloid leukemia (AML) is a heterogeneous disease. One reason for the heterogeneity may originate from inter-individual differences in the responses of leukemic cells to endogenous cytokines. On the basis of mathematical modeling, computer simulations and patient data, we have provided evidence that cytokine-independent leukemic cell proliferation is linked to early relapses and poor overall survival. Depending whether the model of cytokine-dependent or cytokine-independent leukemic cell proliferation fits to the clinical data, patients can be assigned to two groups that differ significantly with respect to overall survival. The modeling approach further enables us to identify parameter constellations that can explain unexpected responses of some patients to external cytokines such as blast crisis or remission without chemotherapy.

cancer biology↗