Biology subjects

Holtman, I. R.

Publications and source records attributed to Holtman, I. R..

6 recordsLinked to original sources

bioRxiv2026

Cell type-specific histone acetylation landscape in Alzheimer's disease reveals a putative role of MITF in microglia

Alzheimer's disease (AD) is characterised by aberrant amyloid beta and tau aggregation, neuroinflammation, demyelination and neurodegeneration, which have been linked to changes in cell-specific gene expression signatures. Among the mechanisms driving cell-type-specific transcriptional changes, histone acetylation plays a central role in regulating gene activity. While global alterations in histone acetylation have been implicated in AD, the contribution of individual cell types to these epigenetic changes remains poorly understood. To decode cell-type-specific changes in gene regulation in AD pathogenesis, we profiled histone H3 lysine 27 acetylation (H3K27ac) in microglia, oligodendrocytes and neurons from the prefrontal cortex of individuals with late-stage AD and non-dementia controls. Oligodendrocytes had the highest number of differential H3K27ac regions in AD, followed by microglia. Genes nearest to differential H3K27ac in purified microglia were enriched for phagocytosis, lipid processing, inflammatory and disease-associated cell state signature genes. Gene network analysis revealed downregulation of homeostatic genes in AD microglia and upregulation of immune activation, including signatures of lipid-handling and monocyte-derived macrophages. Oligodendrocyte co-regulated regions were indicative of increased MHC class I antigen presentation and altered neuron-oligodendrocyte interactions in AD. We identified H3K27ac allele-specific variants (ASVs) enriched near endolysosomal and ubiquitin-proteasome-associated genes in microglia and neurons. ASVs coincided with AD genome-wide association study (GWAS) risk loci, including CLU in oligodendrocytes and HLA-DRB1 in microglia. DNA motif analysis identified putative transcription factor drivers of AD glial dysregulation, including the lysosomal-associated MITF, Cap'n'collar (CNC) family (BACH1 and NFE2) and AP-1 activation in microglia. DNA binding of the MITF protein in human microglia was localised to lysosomal-associated genes and enriched in H3K27ac regions upregulated in AD and near disease-associated microglia (DAM) genes. Collectively, these findings implicate lysosomal dysfunction and upstream transcriptional regulation via MITF as key processes in AD microglia.

neuroscience↗

bioRxiv2024

Notch Signaling Drives Pro-Regenerative and Migratory Traits in Glandular Stem/Progenitor Cells

Organoid models have advanced our understanding of adult stem/progenitor cell dynamics and function. However, uncovering the regulatory mechanisms of scarce and often quiescent stem cells in organs like the salivary glands remains challenging. Using single-cell RNA sequencing and bulk ATAC and RNA-sequencing analysis, we conducted in-depth profiling of the cellular populations and key signaling pathways characterizing a mouse submandibular salivary gland organoid (mSGO) model at different temporal stages and in response to radiation damage. We identified Sox9- and Itgb1-expressing cells as the most primitive adult stem/progenitor populations and uncover novel stemness and migratory roles for Cd44-expressing cells. Moreover, we revealed that Notch signaling is essential for maintaining self-renewal and migration potential of these stem/progenitor cells post-irradiation. Extending these findings to patient-derived mSGOs, as well as murine and patient-derived mammary and thyroid gland organoids, we confirmed Notch signaling as a conserved regulator of stem/progenitor cell function under migrative and regenerative conditions.

cell biology↗

bioRxiv2023

Radiotherapy induces persistent innate immune reprogramming of microglia into a primed state

More than half of all brain tumour survivors experience debilitating and often progressive cognitive decline after treatment with radiotherapy. Microglia, the resident macrophages in the brain, have been implicated in this decline. In response to various insults microglia can develop innate immune memory (IIM), which can either enhance (priming) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigated whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats showed a stronger immune response to a secondary inflammatory insult demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of post-mortem normal-appearing non-tumour brain tissue of glioblastoma patients indicates that radiation-induced microglial priming is conserved in humans. Targeting microglial priming after radiotherapy or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity.

neuroscience↗

bioRxiv2020

Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Mechanisms by which non-coding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million SNPs and InDels provided by five inbred strains of mice on the responses of macrophages to interleukin 4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Remarkably, of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage determining and signal-dependent transcription factors driving late enhancer activation. These studies further revealed mechanisms by which non-coding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

genomics↗

bioRxiv2020

Resident macrophages establish and control lipid stores via PDGFcc production

Macrophages control inflammation in obese animals, and may also directly or indirectly regulate energy storage. In a genetic screen we identify a PDGF-family growth factor, Pvf3, produced by macrophages and required for lipid storage in Drosophila larvaes fat body cells. We next demonstrate using genetic and pharmacological approaches that Pvf3 ortholog PDGFcc, produced by Ccr2-independent embryo-derived tissue macrophages, is also required for storage in mammalian white adipose tissue. PDGFcc production by resident macrophages is regulated by diet, acts on white adipocytes in a paracrine manner, and controls adipocyte hypertrophy in high-fat diet fed and genetically hyperphagic mice. Upon PDGFcc blockade, excess lipids are redirected at the organismal level toward thermogenesis and hepatic storage in adults. This process is altogether independent from inflammation and insulin resistance promoted by Ccr2-dependent monocytes/macrophages. Our data identify a conserved macrophagedependent mechanism that controls energy storage, conducive to the design of pharmacological interventions.

immunology↗

bioRxiv2019

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Unique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimers disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function.\n\nOne Sentence SummaryIdentification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants.

neuroscience↗