Biology subjects

Lang, H.

Publications and source records attributed to Lang, H..

3 recordsLinked to original sources

bioRxiv2021

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.

Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into at least three RMC cell states along an epithelial-mesenchymal gradient through a transcriptional switch involving loss of renal transcription factor TFCP2L1 and gain of a NFE2L2-associated ferroptosis resistance program. SMARCB1 re-expression in cultured RMC cells reactivates TFCP2L1 that relocates SWI/SNF from the promoters of the MYC-driven oncogenic program to the enhancers of TAL identity genes followed by ferroptotic cell death. We further show that RMC is associated with abundant M2-type macrophages and cancer-associated fibroblasts (CAFs) and we identify key regulatory cross-talks that shape this immunosuppressive microenvironment. Together our data describe the molecular events of RMC transformation and identify novel therapeutically targetable vulnerabilities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/462391v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@152fa6eorg.highwire.dtl.DTLVardef@b76f50org.highwire.dtl.DTLVardef@ed1382org.highwire.dtl.DTLVardef@9be54f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea

Glial cells of the auditory nerve regulate formation of the nodes of Ranvier that are needed for regeneration of action potentials and proper hearing function. Here we identify and describe the distinct features of two novel types of Ranvier nodes--the axonal node and the ganglion node--in the mouse auditory nerve that change across the lifespan, including during myelination and postnatal development, and degenerate during aging. Cellular, molecular, and structure-function correlation evaluations revealed that nodal types are critical for different aspects of auditory nerve function. Specifically, the length of the axonal node is associated with neural processing speed and neural synchrony, whereas ganglion node development is associated with amplitude growth of the action potential. Moreover, our data indicate that dysregulation of glial cells and associated degeneration of the ganglion node structure are an important and new mechanism of auditory nerve dysfunction in age-related hearing loss.

neuroscience↗

bioRxiv2020

Honeybee genetics shape the strain-level structure of gut microbiota in social transmission

Honeybee gut microbiota transmitted via social interactions are beneficial to the host health. Although the microbial community is relatively stable, individual variations and high strain-level diversity have been detected across honeybees. Although the bee gut microbiota structure is influenced by environmental factors, the heritability of the gut members and the contribution of the host genetics remains elusive. Considering bees within a colony are not readily genetically identical due to the polyandry of queen, we hypothesize that the microbiota structure can be shaped by host genetics. We used shotgun metagenomics to simultaneously profile the microbiota and host genotypes of individuals from hives of four different subspecies. Gut composition is more distant between genetically different bees at both phylotype- and "sequence-discrete population"-level. We then performed a successive passaging experiment within colonies of hybrid bees generated by artificial insemination, which revealed that the microbial composition dramatically shifts across batches of bees during the social transmission. Specifically, different strains from the phylotype of Snodgrassella alvi are preferentially selected by genetically varied hosts, and strains from different hosts show a remarkably biased distribution of single-nucleotide polymorphism in the Type IV pili loci. A genome-wide association analysis identified that the relative abundance of a cluster of Bifidobacterium strains is associated with the host glutamate receptor gene that is specifically expressed in the bee brain. Finally, mono-colonization of Bifidobacterium with a specific polysaccharide utilization locus impacts the expression and alternative splicing of the gluR-B gene, which is associated with an altered circulating metabolomic profile. Our results indicated that host genetics influence the bee gut composition, and suggest a gut-brain connection implicated in the gut bacterial strain preference. Honeybees have been used extensively as a model organism for social behaviors, genetics, and gut microbiome. Further identification of host genetic function as shaping force of microbial structure will advance our understanding of the host-microbe interactions.

microbiology↗