Biology subjects

Scacheri, P.

Publications and source records attributed to Scacheri, P..

4 recordsLinked to original sources

bioRxiv2021

Distinct cell adhesion signature defines glioblastoma myeloid-derived suppressor cell subsets

Increased myeloid-derived suppressor cell (MDSC) frequency is associated with worse outcomes and poor therapeutic response in glioblastoma (GBM). Monocytic (m) MDSCs represent the predominant subset in the GBM microenvironment. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared to granulocytic (g) MDSCs has yet to be determined. Here, we report that mMDSCs and gMDSCs display differences in their tumoraccelerating ability, with mMDSCs driving tumor growth in GBM models. Epigenetic assessments indicate enhanced gene accessibility for cell adhesion programs in mMDSCs and higher cellsurface integrin expression in mouse and human mMDSCs. Integrin {beta}1 blockage abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment. These findings suggest that integrin {beta}1 expression underlies the enrichment of mMDSCs in tumors and represents a putative immunotherapy target to attenuate myeloid cell-driven immune suppression in GBM. SummaryMyeloid-derived suppressor cells (MDSCs) drive glioblastoma growth; however, the function of specific MDSCs subsets is unclear. Bayik et al. demonstrate that adhesion programs are enhanced in monocytic MDSCs and responsible for their GBM-promoting function.

immunology↗

bioRxiv2019

Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input \"easy Hi-C\" (eHi-C) protocol to map the 3D genome architecture in neurogenesis and brain tissues, and also developed an improved Hi-C bias-correction pipeline (HiCorr) enabling better identification of enhancer loops or aggregates at sub-TAD level. We compared ultra-deep 3D genome maps from 10 human tissue- or cell types, with a focus on stem cells and neural development. We found several large loci in skin-derived human iPSC lines showing recurrent 3D compartmental memory of somatic heterochromatin. Chromatin loop interactions, but not genome compartments, are hallmarks of neural differentiation. Interestingly, we observed many cell type- or differentiation-specific enhancer aggregates spanning large neighborhoods, supporting a phase-separation mechanism that stabilizes enhancer contacts during development. Finally, we demonstrated that chromatin loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.\n\nHighlightsO_LILow input \"easy Hi-C\" protocol compatible with 50-100K cells\nC_LIO_LIImproved Hi-C bias correction allows direct observation and accurate identification of sub-TAD chromatin loops and enhancer aggregates\nC_LIO_LIRecurrent architectural memory of somatic heterochromatin at compartment level in skin-derived hiPSCs\nC_LIO_LIChromatin loop, but not genome compartment, marks neural differentiation\nC_LIO_LIChromatin loop outperforms eQTL in defining brain GWAS target genes\nC_LI

genomics↗

bioRxiv2017

Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer.

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ER)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. In vitro work shows that YY1 is essential for ER transcriptional activity and defines the critical subset of functional ER binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

cancer biology↗

bioRxiv2017

Positively Selected Enhancer Elements Endow Tumor Cells with MetastaticCompetence

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic tumors in human patients as well as nearisogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). We demonstrate that these Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as F3. We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for anti-metastatic therapies.

cancer biology↗