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Current opinion views androgens as the pathogenic driver in the miniaturization of hair follicles of androgenetic alopecia by interfering with the dermal papilla. This cannot be the sole cause and therefore it is important for therapeutic and diagnostic purposes to identify additional pathways. Comparative full transcriptome profile analysis of the hair bulb region of normal and miniaturized hair follicles from vertex and occipital region in males with and without androgenetic alopecia revealed that next to the androgen receptor as well the retinoid receptor and particularly the PPAR pathway is involved in progressive hair miniaturization. We demonstrate the concurrent up-regulation of PPARGC1a in the epithelial compartment and androgen receptor in the dermal papilla of miniaturized hair. Dynamic Ppargc1a expression in the mouse hair cycle suggests a possible role in regulating hair growth and differentiation. This is supported by reduced proliferation of human dermal papilla and predominantly epithelial keratinocytes after incubation with AICAR, the agonist for AMPK signaling which activates PPARGC1a and serves as co-activator of PPARγ. In addition, miRNA profiling shows enrichment of miRNA-targeted genes in retinoid receptors and PPARGC1α/PPARγ signaling, and antigen presentation pathways.

Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date, but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPCs) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPCs in hair-related studies often lack dermal papilla characteristics. In contrast, immortalized DPCs have high resemblance to intact dermal papilla. We derived immortalized human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retained high proportions of dermal papilla signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 (twist family basic helix-loop-helix transcription factor 1) and SSPN (sarcospan) to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularization around the hair follicle may contribute to the development of AGA.

Parkinson disease (PD) is a common neurodegenerative disorder which manifests as bradykinesia, movement rigidity and tremors in affected individuals. Our understanding of the genetic basis of PD has been steadily increasing since the initial report of a-synuclein mutations two decades ago. Mutations implicated in familial PD fully account for monogenic inheritance and point to potential functional mechanisms underlying PD. However, most sporadic PD cannot be accounted for by known familial PD genes, with the late-onset nature of PD making further linkage studies challenging. Genome-wide association and whole exome sequencing studies have implicated a growing list of mutations and genes in PD, which are expected to provide new insights into potential pathways involved in PD pathogenicity. NRF (Natl Research Foundation, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P, Male-pattern baldness is a common condition in which hair is progressively lost from the scalp. Here, the authors find 23 new genetic variants associated with this condition and suggest that it is not an isolated trait but may share an underlying biological basis with various diseases.

Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version

Androgenetic alopecia (AGA) is the most common progressive form of hair loss that occurs in more than half of men above 50 years 1. AGA onset is dependent on genetic predisposition and presence of androgen 2, 3. In AGA patients, hair undergoes shortened anagen phase, progressive miniaturization and subsequent vellus transformation of terminal hair follicle. This article is protected by copyright. All rights reserved.

Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally. Many transcription factors bind to regulatory DNA elements distant from gene promoters. Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor α (ER-α) in the human genome. We found that most high-confidence remote ER-α-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-α functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes. © 2009 Macmillan Publishers Limited. All rights reserved.

Derived from fibroblasts, myofibroblasts are the principal cells that are responsible for the synthesis and reorganization of excess matrix in renal interstitial fibrosis. Recognized from their de novo expression of alpha-smooth muscle actin, myofibroblast differentiation and activity can be influenced by several factors, including a combination of growth factors and other soluble mediators, extracellular matrix components, and mechanical stress. Relaxin has previously been shown to inhibit renal myofibroblast differentiation in vitro, an effect partly mediated through its ability to interfere with the transforming growth factor-beta1 (TGF-beta1) pathway via inhibition of Smad2 phosphorylation and translocation. Furthermore, endogenous relaxin has been shown to protect the kidney from a myofibroblast-mediated model of injury in vivo. However, the pathways involved in the interaction between relaxin and TGF-beta1 remain unknown. In this report, the inhibitory actions of relaxin on TGF-beta1-induced renal myofibroblast differentiation are summarized to date, and the potential signaling pathways that are implicated in relaxin's inhibitory actions are discussed.

MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.

The hormone, relaxin, inhibits aberrant myofibroblast differentiation and collagen deposition by disrupting the TGF-β1/Smad2 axis, via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), extracellular signal-regulated kinase (ERK)1/2 phosphorylation (pERK) and a neuronal nitric oxide (NO) synthase (nNOS)-NO-cyclic guanosine monophosphate (cGMP)-dependent pathway. However, the signalling pathways involved in its additional ability to increase matrix metalloproteinase (MMP) expression and activity remain unknown. This study investigated the extent to which the NO pathway was involved in human gene-2 (H2) relaxin's ability to positively regulate MMP-1 and its rodent orthologue, MMP-13, MMP-2 and MMP-9 (the main collagen-degrading MMPs) in TGF-β1-stimulated human dermal fibroblasts and primary renal myofibroblasts isolated from injured rats; by gelatin zymography (media) and Western blotting (cell layer). H2 relaxin (10–100 ng/ml) significantly increased MMP-1 (by ∼50%), MMP-2 (by ∼80%) and MMP-9 (by ∼80%) in TGF-β1-stimulated human dermal fibroblasts; and MMP-13 (by ∼90%), MMP-2 (by ∼130%) and MMP-9 (by ∼115%) in rat renal myofibroblasts (all p

Mammalian genomes are viewed as functional organizations that orchestrate spatial and temporal gene regulation. CTCF, the most characterized insulator-binding protein, has been implicated as a key genome organizer. However, little is known about CTCF-associated higher-order chromatin structures at a global scale. Here we applied chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing to elucidate the CTCF-chromatin interactome in pluripotent cells. From this analysis, we identified 1,480 cis- and 336 trans-interacting loci with high reproducibility and precision. Associating these chromatin interaction loci with their underlying epigenetic states, promoter activities, enhancer binding and nuclear lamina occupancy, we uncovered five distinct chromatin domains that suggest potential new models of CTCF function in chromatin organization and transcriptional control. Specifically, CTCF interactions demarcate chromatin-nuclear membrane attachments and influence proper gene expression through extensive cross-talk between promoters and regulatory elements. This highly complex nuclear organization offers insights toward the unifying principles that govern genome plasticity and function.

Delineating candidate genes at the chromosomal breakpoint regions in the apparently balanced chromosome rearrangements (ABCR) has been shown to be more effective with the emergence of next-generation sequencing (NGS) technologies. We employed a large-insert (7–11 kb) paired-end tag sequencing technology (DNA-PET) to systematically analyze genome of four patients harbouring cytogenetically defined ABCR with neurodevelopmental symptoms, including developmental delay (DD) and speech disorders. We characterized structural variants (SVs) specific to each individual, including those matching the chromosomal breakpoints. Refinement of these regions by Sanger sequencing resulted in the identification of five disrupted genes in three individuals: guanine nucleotide binding protein, q polypeptide (GNAQ), RNA-binding protein, fox-1 homolog (RBFOX3), unc-5 homolog D (C.elegans) (UNC5D), transmembrane protein 47 (TMEM47), and X-linked inhibitor of apoptosis (XIAP). Among them, XIAP is the causative gene for the immunodeficiency phenotype seen in the patient. The remaining genes displayed specific expression in the fetal brain and have known biologically relevant functions in brain development, suggesting putative candidate genes for neurodevelopmental phenotypes. This study demonstrates the application of NGS technologies in mapping individual gene disruptions in ABCR as a resource for deciphering candidate genes in human neurodevelopmental disorders (NDDs).

Nat. Genet. 43, 630–638 (2011); published online 19 June; corrected after print 11 July 2011 In the version of this article initially published, the accession codes section contained inaccuracies. The raw sequences and processed data generated from this study can be downloaded with accession number GSE28247.