Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Despite developments in targeted gene sequencing and whole-genome analysis techniques, the robust detection of all genetic variation, including structural variants, in and around genes of interest and in an allele-specific manner remains a challenge. Here we present targeted locus amplification (TLA), a strategy to selectively amplify and sequence entire genes on the basis of the crosslinking of physically proximal sequences. We show that, unlike other targeted re-sequencing methods, TLA works without detailed prior locus information, as one or a few primer pairs are sufficient for sequencing tens to hundreds of kilobases of surrounding DNA. This enables robust detection of single nucleotide variants, structural variants and gene fusions in clinically relevant genes, including BRCA1 and BRCA2, and enables haplotyping. We show that TLA can also be used to uncover insertion sites and sequences of integrated transgenes and viruses. TLA therefore promises to be a useful method in genetic research and diagnostics when comprehensive or allele-specific genetic information is needed.
A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer de Bruyn, M. (2019). A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer. Cancer immunology research, 7(5), 784-796.
AbstractThe chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the transforming growth factor beta (TGFβ)-dependent CD103 + CD8 + tumor-infiltrating T-cell (TIL) subpopulation expressed and produced CXCL13. Accordingly, CD8 + T cells from peripheral blood activated in the presence of TGFβ upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGFβ receptor signaling abrogated CXCL13 production. CXCL13 + CD103 + CD8 + TILs correlated with B-cell recruitment, TLSs, and neoantigen burden in six cohorts of human tumors. Altogether, our findings indicated that TGFβ plays a non-canonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13 + CD103 + CD8 + TILs in mediating B-cell recruitment and TLS formation in human tumors.
In conclusion, this large deceased donor study shows enrichment of hypoxia and complement-and-coagulation pathways already in DBD donors before cessation of blood flow, before organ retrieval. Therefore, future intervention therapies should target hypoxia and complement-and-coagulation cascades in the donor to improve renal allograft outcome in the recipient.
The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neu gene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu-overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.
Imbalances of 3p telomeric sequences cause 3p- and trisomy 3p syndrome, respectively, showing distinct, but also shared clinical features. No causative genes have been identified in trisomy 3p patients, but for the 3p- syndrome, there is growing evidence that monosomy for one or more of four genes at 3pter, CHL1, CNTN4, CRBN, and MEGAP/srGAP3, may play a causative role. We describe here an analysis of a complex chromosome 3p aberration in a severely mentally retarded patient that revealed two adjacent segments with different copy number gains and a distal deletion. The deletion in this patient included the loci for CHL1, CNTN4, and CRBN, and narrowed the critical segment associated with the 3p- syndrome to 1.5 Mb, including the loci for CNTN4 and CRBN. We speculate that the deletion contributes more to this patient's phenotype than the gains that were observed. We suggest that 3p- syndrome associated features are primarily caused by loss of CNTN4 and CRBN, with loss of CHL1 probably having an additional detrimental effect on the cognitive functioning of the present patient.
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