Applications of Morphochronology to the Active Tectonics of Tibet

The Himalayas and the Tibetan Plateau were formed as a result of the collision of India and Asia, and provide an excellent opportunity to study the mechanical response of the continental lithosphere to tectonic stress. Geophysicists are divided in their views on the nature of this response advocating either (1) homogeneously distributed deformation with the lithosphere deforming as a fluid continuum or (2) deformation is highly localized with the lithosphere that deforms as a system of blocks. The resolution of this issue has broad implications for understanding the tectonic response of continental lithosphere in general. Homogeneous deformation is supported by relatively low decadal, geodetic slip-rate estimates for the Altyn Tagh and Karakorum Faults. Localized deformation is supported by high millennial, geomorphic slip-rates constrained by both cosmogenic and radiocarbon dating on these faults. Based upon the agreement of rates determined by radiocarbon and cosmogenic dating, the overall linearity of offset versus age correlations, and on the plateau-wide correlation of landscape evolution and climate history, the disparity between geomorphic and geodetic slip-rate determinations is unlikely to be due to the effects of surface erosion on the cosmogenic age determinations. Similarly, based upon the consistency of slip-rates over various observation intervals, secular variations in slip-rate appear to persist no longer than 2000 years and are unlikely to provide reconciliation. Conversely, geodetic and geomorphic slip-rate estimates on the Kunlun fault, which does not have significant splays or associated thrust faults, are in good agreement, indicating that there is no fundamental reason why these complementary geodetic and geomorphic methods should disagree. Similarly, the geodetic and geomorphic estimates of shortening rates across the northeastern edge of the plateau are in reasonable agreement, and the geomorphic rates on individual thrust faults demonstrate a significant eastward decrease in the shortening rate. This rate decrease is consistent with the transfer of slip from the Altyn Tagh Fault (ATF) to genetically-related thrust mountain building at its terminus. Rates on the ATF suggest a similar decrease in rate, but the current data set is too small to be definitive. Overall, the high, late Pleistocene-Holocene, geomorphic slip velocities on the major strike-slip faults of Tibet, suggests that they absorb as much of India's convergence relative to Siberia as the Himalayan Main Frontal Thrust on the southern edge of the plateau

Genomic mapping of 5-hydroxymethylcytosine in the human brain

Methylation at the 5-position of cytosine is a well-studied epigenetic pathway. In addition to 5-methylcytosine (5mC), substantial amounts of 5-hydroxymethylcytosine (5hmC) also referred to as the sixth DNA base have been detected in certain tissues, most notably the brain. However, the genomic distribution of this cytosine modification is unknown. Here, we have used an immunoprecipitation technique (5hmC-IP) to examine the occurrence of 5hmC in DNA from human brain frontal lobe tissue. The distribution of 5hmC was compared to that of 5mC. We show that 5hmC is more selectively targeted to genes than is 5mC. 5hmC is particularly enriched at promoters and in intragenic regions (gene bodies) but is largely absent from non-gene regions. 5hmC peaks at transcription start sites did not correlate with gene expression levels for promoters with intermediate or high CpG content. However, the presence of 5hmC in gene bodies was more positively correlated with gene expression levels than was the presence of 5mC. Promoters of testis-specific genes showed strong 5mC peaks in brain DNA but were almost completely devoid of 5hmC. Our data provide an overview of the genomic distribution of 5hmC in human brain and will set the stage for further functional characterization of this novel DNA modification

Relationship between Gene Body DNA Methylation and Intragenic H3K9me3 and H3K36me3 Chromatin Marks

To elucidate the relationship between intragenic DNA methylation and chromatin marks, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). Analysis of H3K36me3 profiles indicated that this intragenic mark of active genes is associated with two categories of genes: (i) genes with low CpG density and H3K9me3 in the gene body or (ii) genes with high CpG density and DNA methylation in the gene body. We observed that a combination of low CpG density in gene bodies together with H3K9me3 and H3K36me3 occupancy is a specific epigenetic feature of zinc finger (ZNF) genes, which comprise 90% of all genes carrying both histone marks on chromosome 19. For genes with high intragenic CpG density, transcription and H3K36me3 occupancy were not changed in conditions of partial or intensive loss of DNA methylation in gene bodies. siRNA knockdown of SETD2, the major histone methyltransferase responsible for production of H3K36me3, did not reduce DNA methylation in gene bodies. Our study suggests that the H3K36me3 and DNA methylation marks in gene bodies are established largely independently of each other and points to similar functional roles of intragenic DNA methylation and intragenic H3K9me3 for CpG-rich and CpG-poor genes, respectively

Investigating the Epigenetic Effects of a Prototype Smoke-Derived Carcinogen in Human Cells

Global loss of DNA methylation and locus/gene-specific gain of DNA methylation are two distinct hallmarks of carcinogenesis. Aberrant DNA methylation is implicated in smoking-related lung cancer. In this study, we have comprehensively investigated the modulation of DNA methylation consequent to chronic exposure to a prototype smoke-derived carcinogen, benzo[a]pyrene diol epoxide (B[a]PDE), in genomic regions of significance in lung cancer, in normal human cells. We have used a pulldown assay for enrichment of the CpG methylated fraction of cellular DNA combined with microarray platforms, followed by extensive validation through conventional bisulfite-based analysis. Here, we demonstrate strikingly similar patterns of DNA methylation in non-transformed B[a]PDE-treated cells vs control using high-throughput microarray-based DNA methylation profiling confirmed by conventional bisulfite-based DNA methylation analysis. The absence of aberrant DNA methylation in our model system within a timeframe that precedes cellular transformation suggests that following carcinogen exposure, other as yet unknown factors (secondary to carcinogen treatment) may help initiate global loss of DNA methylation and region-specific gain of DNA methylation, which can, in turn, contribute to lung cancer development. Unveiling the initiating events that cause aberrant DNA methylation in lung cancer has tremendous public health relevance, as it can help define future strategies for early detection and prevention of this highly lethal disease

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption