Biology subjects

Su, Y.

Publications and source records attributed to Su, Y..

4 recordsLinked to original sources

bioRxiv2018

Fate Before Function: Specification of the Hair Follicle Niche Occurs Prior to its Formation and Is Progenitor Dependent

Cell fate transitions are essential for specialization of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we show that dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes, are specified before niche formation and function. With 3D/4D microscopy we identify unclustered DC precursors. With population-based and single-cell transcriptomics we define a molecular time-lapse of dynamic niche signatures and the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then consolidate DC niche formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for DC-precursor specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/414839_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (78K):\norg.highwire.dtl.DTLVardef@13fa73aorg.highwire.dtl.DTLVardef@1fbd280org.highwire.dtl.DTLVardef@1b8f66borg.highwire.dtl.DTLVardef@3a1ef9_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIPrecursors of the hair follicle niche are specified before niche cluster formation\nC_LIO_LIBulk/single cell RNA-seq defines early niche fate at molecular transitional state\nC_LIO_LISuccessive waves of transcription factor/signaling genes mark niche fate acquisition\nC_LIO_LINiche fate acquisition is not \"pre-programmed\" and requires FGF20 from progenitors\nC_LI

developmental biology↗

bioRxiv2018

Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the real or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQ1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 x 10-36, OR=2.29). Further stepwise conditional analysis revealed that DR{beta}1:37N has an independent protective effect on ACPA-positive RA (P = 5.81 x 10-16, OR=0.49). The DQ1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 x 10-5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQ1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DR{beta}1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.\n\nIn this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

genetics↗

bioRxiv2017

Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation

Growth differentiation factor 8 (GDF8)/Myostatin is a latent TGF{-}{beta} family member that potently inhibits skeletal muscle growth. Here, we compared the conformation and dynamics of precursor, latent, and Tolloid{-}cleaved GDF8 pro{-}complexes to understand structural mechanisms underlying latency and activation of GDF8. Negative stain electron microscopy (EM) of precursor and latent pro{-}complexes reveals a V{-}shaped conformation that is unaltered by furin cleavage and sharply contrasts with the ring{-}like, cross{-}armed conformation of latent TGF{-}{beta}1. Surprisingly, Tolloid{-}cleaved GDF8 does not immediately dissociate, but in EM exhibits structural heterogeneity consistent with partial dissociation. Hydrogen-deuterium exchange was not affected by furin cleavage. In contrast, Tolloid cleavage, in the absence of prodomain-growth factor dissociation, increased exchange in regions that correspond in pro-TGF-{beta}1 to the 1-helix, latency lasso, and {beta}1 strand in the prodomain and to the {beta}6-7 strands in the growth factor. Thus, these regions are important in maintaining GDF8 latency. Our results show that Tolloid cleavage activates latent GDF8 by destabilizing specific prodomain-growth factor interfaces and primes the growth factor for release from the prodomain.

biochemistry↗

bioRxiv2017

Necroptosis promotes the Aging of the Male Reproductive System in Mice

Necroptosis is a form of programmed necrotic cell death in mammals that is mediated by a pair of kinases, RIP1 and RIP3, as well as the RIP3 substrate MLKL. We report here that male reproductive organs of both RIP3-and MLKL-knockout mice retain \"youthful\" morphology and function into advanced age, while those of age-matched wild type mice deteriorate. The RIP3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild type mice. When the testes of young wild type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild type mice with an RIP1 inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice.

cell biology↗