Biology subjects

Wu, W.

Publications and source records attributed to Wu, W..

At least 19 recordsLinked to original sources

bioRxiv2018

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NF{kappa};B activating protein (NKAP) and limits NF{kappa}B activation to suppress expression of PDHK1, a NF{kappa}B target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.\n\nSIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

cancer biology↗

bioRxiv2018

Diffusion Acceleration with Gaussian process Estimated Reconstruction (DAGER)

PurposeImage acceleration provides multiple benefits to diffusion MRI (dMRI), with in-plane acceleration reducing distortion and slice-wise acceleration increasing the number of directions that can be acquired in a given scan time. However, as acceleration factors increase, the reconstruction problem becomes ill-conditioned, particularly when using both in-plane acceleration and simultaneous multi-slice (SMS) imaging. In this work, we develop a novel reconstruction method for in-vivo MRI acquisition that provides acceleration beyond what conventional techniques can achieve.\n\nTheory and MethodsWe propose to constrain the reconstruction in the spatial (k) domain by incorporating information from the angular (q) domain. This approach exploits smoothness of the signal in q-space using Gaussian processes, as has previously been exploited in post-reconstruction analysis. We demonstrate in-plane acceleration exceeding the theoretical parallel imaging limits, and SMS combined with in-plane acceleration at a total factor of 12. This reconstruction is cast within a Bayesian framework that incorporates estimation of smoothness hyper-parameters, with no need for manual tuning.\n\nResultsSimulations and in vivo results demonstrate superior performance of the proposed method compared with conventional parallel imaging methods. These improvements are achieved without loss of spatial or angular resolution and require only a minor modification to standard pulse sequences.\n\nConclusionThe proposed method provides improvements over existing methods for diffusion acceleration, particularly for high SMS acceleration with in-plane undersampling.

neuroscience↗

bioRxiv2018

Multimodal interferometric imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm

We present a multimodal label-free interferometric imaging platform for measuring intracellular nanoscale structure and macromolecular dynamics in living cells with a sensitivity to macromolecules as small as 20nm and millisecond temporal resolution. We validate this system by pairing experimental measurements of nanosphere phantoms with a novel interferometric theory. Applying this system in vitro, we explore changes in higher-order chromatin structure and dynamics that occur due to cellular fixation, stem cell differentiation, and ultraviolet (UV) light irradiation. Finally, we discover a new phenomenon, cellular paroxysm, a near-instantaneous, synchronous burst of motion that occurs early in the process of UV induced cell death. Given this platforms ability to obtain nanoscale sensitive, millisecond resolved information within live cells without concerns of photobleaching, it has the potential to answer a broad range of critical biological questions about macromolecular behavior in live cells, particularly about the relationship between cellular structure and function.

biophysics↗

bioRxiv2018

Evaluation of the antifibrotic potency by knocking down SPARC, CCR2 and SMAD3

The genes of SPARC, CCR2, and SMAD3 are implicated in orchestrating inflammation and fibrosis in scleroderma and other fibrotic disorders. Aim of the studies was to examine synergistic effect of inhibition of these genes in treating fibrosis. The peptide nanoparticles were used to deliver the siRNAs in bleomycin-induced fibrotic mice. Triple combination of siRNAs targeting on Sparc, Ccr2 and Smad3 achieved favorable anti-inflammatory and anti-fibrotic effects. Inhibition of inflammation was evidenced by reduced inflammatory cells and proinflammatory cytokines in the BALF and/or the tissues. Activation of fibroblasts was suppressed in mouse tissues in which -Sma and collagens were significantly reduced. Aberrant expression of the genes in fibroblasts, monocytes/macrophage, endothelial and epithelial cells were reinstalled after the treatment. In addition, transcriptome profiles indicated that some bleomycin-induced alterations of multiple biological pathways were recovered to varying degrees by the treatment. The results indicated that the triple combination of siRNAs systemically reinstated multiple biopathways, probably through controlling on different cell types including fibroblasts, monocytes/macrophages, endothelial cells and others. The multi-target-combined therapeutic approach examined herein may represent a novel and effective therapy for fibrosis.

molecular biology↗

bioRxiv2018

Co-occurring genetic alterations in the RAS pathway promote resistance to MET inhibitor treatment in non-small cell lung cancer with a MET exon 14 skipping mutation

PURPOSEWhile patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.\n\nMETHODSTargeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.\n\nRESULTSProminent co-occurring RAS-MAPK pathway gene alterations (e.g. in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared to EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib.\n\nCONCLUSIONOur study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

cancer biology↗

bioRxiv2018

Identification of Novel Genes and Variations Associated to Glycolytic Potential Based on Pig Model

In livestock, glycolytic potential (GP) is a critical indicator for evaluating the meat quality. To date, two major genes protein kinase AMP-activated {gamma}3 non-catalytic subunit gene (PRKAG3) and phosphorylase kinase catalytic subunit gamma 1(PHKG1), and corresponding cause mutations influencing GP have been confirmed in pigs. Therefore, the aim of this study to identify the novel candidate genes and variations related to GP-related traits using a four-hybrid pig model [Pietrain (P)x Duroc (D)] x[(Landrace) x(Yorkshire)]. We totally constructed six RNA-seq libraries using longissimus dorsi (LD) muscles, and each library contained two higher GP (H) or two lower GP (L) individuals. A total of 525, 698 and 135 differentially expressed genes (DEGs) were identified between H11 vs L11, H9 vs L9, and H5 vs L5 groups using PossionDis method, respectively. Notably, we found 97 non-redundant DEGs were mapped to GP related QTLs from three paired comparison groups. Moreover, 69 DEGs were identified between H (H11, H9 and H5) and L (L11, L9 and L5) groups using NOIseq method. Additionally, 1,076 potential specific SNPs were figured out between H and L groups, and approximately 40 large Indels with a length [≥] 5bp were identified in each sequencing library. In conclusion, our data provide foundation for further confirming the key genes and the functional mutations affecting GP-related traits in pigs, and also pave the way for elucidating the underling molecular regulatory mechanisms of glycogen metabolism in future study. Moreover, this study might provide valuable information for study on human glycogen storage diseases.

genomics↗

bioRxiv2018

A computational strategy for finding novel targets and therapeutic compounds for opioid dependence

Opioids are widely used for treating different types of pains, but overuse and abuse of prescription opioids have led to opioid epidemic in the United States. Besides analgesic effects, chronic use of opioid can also cause tolerance, dependence, and even addiction. Effective treatment of opioid addiction remains a big challenge today. Studies on addictive effects of opioids focus on striatum, a main component in the brain responsible for drug dependence and addiction. Some transcription regulators have been associated with opioid addiction, but relationship between analgesic effects of opioids and dependence behaviors mediated by them at the molecular level has not been thoroughly investigated. In this paper, we developed a new computational strategy that identifies novel targets and potential therapeutic molecular compounds for opioid dependence and addiction. We employed several statistical and machine learning techniques and identified differentially expressed genes over time which were associated with dependence-related behaviors after exposure to either morphine or heroin, as well as potential transcription regulators that regulate these genes, using time course gene expression data from mouse striatum. Moreover, our findings revealed that some of these dependence-associated genes and transcription regulators are known to play key roles in opioid-mediated analgesia and tolerance, suggesting that an intricate relationship between opioid-induce pain-related pathways and dependence may develop at an early stage during opioid exposure. Finally, we determined small compounds that can potentially target the dependence-associated genes and transcription regulators. These compounds may facilitate development of effective therapy for opioid dependence and addiction. We also built a database (http://daportals.org) for all opioid-induced dependence-associated genes and transcription regulators that we discovered, as well as the small compounds that target those genes and transcription regulators.

systems biology↗

bioRxiv2018

HERC2 promotes BLM and WRN to suppress G-quadruplex DNA

BLM and WRN are RecQ DNA helicases essential for genomic stability. Here we demonstrate that HERC2, a HECT E3 ligase, is critical for their functions to suppress G-quadruplex (G4) DNA. HERC2 interacts with BLM, WRN, and replication protein A (RPA) complexes during S-phase of the cell cycle. Depletion of HERC2 dissociates RPA from BLM and WRN complexes and significantly increases G4 formation. Triple depletion revealed that HERC2 has an epistatic relationship with BLM and WRN in their G4- suppressing function. In vitro, HERC2 releases RPA onto single-stranded DNA (ssDNA), rather than anchoring onto RPA-coated ssDNA. CRISPR/Cas9-mediated deletion of the catalytic ubiquitin-binding site of HERC2 causes RPA accumulation in the helicase complexes and increases G4, indicating an essential role for E3 activity in G4 suppression. Both HERC2 depletion and E3 inactivation sensitize cells to the G4-interacting compounds, telomestatin and pyridostatin. Overall, HERC2 is a master regulator of G4 suppression and affects the sensitivity of cells to G4 stabilizers.

molecular biology↗

bioRxiv2018

Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoeba Balamuthia mandrillaris

Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris - a proliferative trophozoite form and a non-proliferative cyst form, which is highly resistant to harsh physical and chemical conditions - have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multi-drug regimens often including the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more effective treatments, we screened 2,177 clinically-approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline, which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a physiologically relevant range. We compare the in vitro efficacy of nitroxoline to drugs currently used in the standard of care for GAE and find that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at physiologically relevant concentrations. Together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections.\n\nImportanceBalamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This study addresses the need for new anti-amoebic drugs using a high-throughput screening approach to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at physiologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life threatening B. mandrillaris infections.

pharmacology and toxicology↗

bioRxiv2018

Overexpressed microRNA-141-3p enhance proliferation via targeting PLAG1 in non-diabetic macrosomia

Several studies have shown microRNAs (miRNAs) could regulate the placental development, yet the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. The key miRNA that abnormal expressed in NDFMS placentas was screened out by miRNA microarray and verified using qRT-PCR in 91 subjects. The effects of the key miRNA were verified by proliferation assay and invasion assay in HTR-8/SVneo cell, and also in pregnant C57BL/6J mice. miR-141-3p was determined as the key miRNA with the most significant difference, which could promote the proliferation and invasion by regulating the expression of target gene PLAG1. Overexpression of PLAG1 could reverse the effect of cell proliferation and invasion ability caused by miR-141-3p overexpression. Significant difference in fetal birth weight was observed between the control group and treated group with miR-141-3p agomir in late pregnancy, but not in early pregnancy. This study revealed miR-141-3p could increase the proliferation of placenta to participate in the occurrence and development of NDFMS through regulating PLAG1 expression.

developmental biology↗

bioRxiv2018

Coupled Mixed Model for joint genetic analysis of complex disorders from independently collected data sets: application to Alzheimer’s disease and substance use disorder

In the last decade, Genome-wide Association studies (GWASs) have contributed to decoding the human genome by uncovering many genetic variations associated with various diseases. Many follow-up investigations involve joint analysis of multiple independently generated GWAS data sets. While most of the computational approaches developed for joint analysis are based on summary statistics, the joint analysis based on individual-level data with consideration of confounding factors remains to be a challenge. In this study, we propose a method, called Coupled Mixed Model (CMM), that enables a joint GWAS analysis on two independently collected sets of GWAS data with different phenotypes. The CMM method does not require the data sets to have the same phenotypes as it aims to infer the unknown phenotypes using a set of multivariate sparse mixed models. Moreover, CMM addresses the confounding variables due to population stratication, family structures, and cryptic relatedness, as well as those arising during data collection such as batch effects that frequently appear in joint genetic studies. We evaluate the performance of CMM using simulation experiments. In real data analysis, we illustrate the utility of CMM by an application to evaluating common genetic associations for Alzheimers disease and substance use disorder using datasets independently collected for the two complex human disorders. Comparison of the results with those from previous experiments and analyses supports the utility of our method and provides new insights into the diseases.\n\nThe software is available at https://github.com/HaohanWang/CMM

genetics↗

bioRxiv2018

Regulation of neural stem cell fate by the transcriptional repressor Capicua

Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cics function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more weakly expressed in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we show that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage selection effects in the developing brain are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal and tumorigenicity. Our results identify Cic is an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.

cancer biology↗

bioRxiv2018

Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2

Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-{kappa}B pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.\n\nIMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-{kappa}B signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.

cancer biology↗

bioRxiv2018

Single-cell transcriptome of antler stem cells from antlerogenic periosteum

Antler regeneration, a stem cell-based epimorphic process, has potential as a valuable model for regenerative medicine. A pool of antler stem cells (ASCs) for antler development is located in the antlerogenic periosteum (AP). However, whether this ASC pool is homogenous or heterogeneous has not been fully evaluated. In this study, we produced a comprehensive transcriptome dataset at the single-cell level for the ASCs based on the 10x Genomics platform (scRNA-seq). A total of 4,565 ASCs were sequenced and classified into a large cell cluster, indicating that the ASCs resident in the AP are likely to be a homogeneous population. The scRNA-seq data revealed that tumor-related genes were highly expressed in these homogeneous ASCs: i.e. TIMP1, TMSB10, LGALS1, FTH1, VIM, LOC110126017 and S100A4. Results of screening for stem cell markers suggest that the ASCs may be considered as a special type of stem cell between embryonic (CD9) and adult (CD29, CD90, NPM1 and VIM) stem cells. Our results provide the first comprehensive transcriptome analysis at the single-cell level for the ASCs, and identified only one major cell type resident in the AP and some key stem cell genes, which may hold the key to why antlers, the unique mammalian organ, can fully regenerate once lost.

cell biology↗

bioRxiv2017

Ennet: exert enhaner-only somatic mutations to discover potential cancer-driving biological networks

Whole genome sequencing technology has facilitated the discovery of a large number of somatic mutations in enhancers (SMEs), whereas the utility of SMEs in tumorigenesis has not been fully explored. Here we present Ennet, a method to comprehensively investigate SMEs enriched networks (SME-networks) in cancer by integrating SMEs, enhancer-gene interactions and gene-gene interactions. Using Ennet, we performed a pan-cancer analysis in 2004 samples from 8 cancer types and found many well-known cancer drivers were involved in the SME-networks, including ESR1, SMAD3, MYC, EGFR, BCL2 and PAX5. Meanwhile, Ennet also identified many new networks with less characterization but have potentially important roles in cancer, including a large SME-network in medulloblastoma (MB), which contains genes enriched in the glutamate receptor and neural development pathways. Interestingly, SME-networks are specific across cancer types, and the vast majority of the genes identified by Ennet have few mutations in gene bodies. Collectively, our work suggests that using enhancer-only somatic mutations can be an effective way to discover potential cancer-driving networks. Ennet provides a new perspective to explore new mechanisms for tumor progression from SMEs.

bioinformatics↗

bioRxiv2017

Influence of APOA5 locus on the treatment efficacy of three statins: evidence from a randomized pilot study in Chinese subjects

Pharmacogenetics or pharmacogenomics approaches are important for addressing the individual variabilities of drug efficacy especially in the era of precision medicine. One particular interesting gene to investigate is APOA5 which has been repeatedly linked with the inter-individual variations of serum triglycerides. Here, we explored APOA5-statin interactions in 195 Chinese subjects randomized to rosuvastatin (5-10 mg/day), atorvastatin (10-20 mg/day), or simvastatin (40 mg/day) for 12 weeks by performing a targeted genotyping analysis of the APOA5 promoter SNP rs662799 (-1131T>C). There were no significant differences between the treatment arms for any of the statin-induced changes in clinical biomarkers. Reductions in LDL cholesterol were influenced by the APOA5 genotype in all three treatment groups. By contrast, changes in HDL cholesterol and triglycerides were only affected by the APOA5 genotype in the atorvastatin and simvastatin groups and not in the rosuvastatin group. Our results support earlier findings indicating that rosuvastatin is a better treatment option and that future studies should consider stratifying subjects not only by genetic background but also by statin type.\n\nAbbreviations

clinical trials↗

bioRxiv2017

Parental allele-specific genome architecture and transcription during the cell cycle

A normal human somatic cell inherits two haploid genomes. Individual chromosomes of each pair have distinct parental origins and parental alleles are known to unequally contribute to cellular function. We integrated chromosome conformation (form) and gene transcription (function) analyses to dissect the dynamics of the maternal and paternal genomes in lymphoblastoid cells during the cell cycle. We found a distinct set of homologous alleles with very different activity often located close to boundaries of euchromatin and heterochromatin domains. We also identified a set of allele-biased topologically associating domains (TADs) that were small sized and had higher gene density. Thousands of genes show allelically biased expression (ABE) with false discovery rate < 0.05, and 98% of them have no allelic switching during G1, S, and G2/M phases. A subset of ABE genes are preferentially localized near TAD boundaries, enriched with chromatin organization transcription factor binding sites, and contained higher number of sequence variants in CCCTC-binding factor sites. Our results extend previous findings of sequence variation as a basis for unequal functional parental genomes. Investigation of haplotype-resolved form-function dynamics may further our understanding of phenotypic traits, genetic diseases, vulnerability to complex disorders, and the development of cancers.

genomics↗

bioRxiv2017

Novel transcriptional activity and extensive allelic imbalance in the human MHC region

The major histocompatibility complex (MHC) region encodes human leukocyte antigen (HLA) genes and is the most complex region in the human genome. The extensive polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known genes, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein coding human endogenous retrovirus genes. We revealed extensive allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Further, we showed that the transcriptome within the MHC region can be defined by 14 distinct co-expression clusters, with evidence of co-regulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.

genomics↗