Biology subjects

Koettgen, A.

Publications and source records attributed to Koettgen, A..

5 recordsLinked to original sources

bioRxiv2026

Loss of the Y chromosome is transcriptionally silent in clear cell renal cell carcinoma and across cancer entities

Tumors in men often lose the Y chromosome. In some tumor types, this is predictive of poor outcome. Given the male predominance and high LOY frequency in clear cell renal cell carcinoma (ccRCC), we asked whether LOY might impact the transcriptome of ccRCC. We determined somatic Y chromosome status and performed differential expression analysis on tumor RNA-sequencing samples of two human ccRCC cohorts (TCGA-KIRC, CPTAC-ccRCC) and in an autochthonous murine ccRCC model with renal epithelium-specific deletion of Vhl, Trp53 and Rb1. We additionally derived five isogenic Y-deficient and five Y chromosome-retaining clones of the human ccRCC cell line 786-O. Across all three settings, transcriptional changes were largely restricted to the expected gene dosage effects of male-specific Y (MSY) and pseudoautosomal region (PAR) genes, without large effects on autosomal genes. At the pathway level, we identified a modest but reproducible response in the human cohorts, converging on cell cycle, ribosomal biogenesis and DNA repair genes. A pan-cancer meta-analysis across TCGA entities recovered the same pattern, with no autosomal gene showing a large consistent effect. In some entities, but not in ccRCC, cancer/testis antigen expression was higher in LOY tumors. We conclude that, apart from direct gene dosage, modest pathway-level shifts and altered silencing of cancer/testis antigens, LOY is transcriptionally silent in adult humans and mice. Y-chromosomal genes are therefore unlikely to act as transcriptional drivers of ccRCC and other cancer entities.

cancer biology↗

bioRxiv2026

Distinct effects of hypomorphic IFT and dynein-2 skeletal ciliopathy disease alleles on chondrogenic differentiation, ECM composition and wnt signalling in ATDC5 derived cartilage-like organoids

Dysfunction of ciliary intraflagellar transport (IFT) and dynein-2 genes causes severe developmental defects, including skeletal phenotypes characterized by shortened ribs and long bones and polydactyly. Specific gene-phenotype associations suggest individual functions of the different IFT/dynein-2 proteins in development. Since null models disrupt ciliogenesis and hence are not suitable to study individual protein functions, we recreated human hypomorphic disease alleles in IFT-A (IFT43 p.M1V), IFT-B (IFT74 deletion of exon 2), and dynein-2 (WDR60 p.A911V), alongside a WDR60 null model in ATDC5 chondrocyte precursor cells. Hypomorphic mutants did not show alterations in ciliation efficiency or cilia length but displayed distinct defects in IFT88 localization, indicating impaired intraflagellar transport. Despite altered IFT, Hedgehog signalling responses were variably affected across the different genotypes. Transcriptomic analysis revealed concurrent increases in canonical Wnt signalling and expression of genes related to late skeletal development in WDR60 A911V and IFT74 del ex 2 mutants, but not in IFT43 M1V or WDR60 loss-of-function mutants. These changes were accompanied by alterations in ECM composition. In addition, all hypomorphic mutants showed reduced levels of the non-canonical Wnt ligand WNT5A in ECM proteomic analyses. Interestingly, loss of cilia in WDR60 loss-of-function mutants had only modest effects on chondrogenic differentiation and ECM composition. Overall, our data provide new evidence of genotype-dependent altered ECM composition as well as dysregulation of canonical and non-canonical Wnt signalling and accelerated chondrocyte differentiation in skeletal ciliopathies. Furthermore, our findings suggest a modulatory rather than essential role of the primary cilium for ATDC5 cell differentiation.

cell biology↗

bioRxiv2022

Multi-omic Analysis of Primary Human Kidney Tissues Identifies Medulla-Specific Gene Expression Patterns

The renal medulla is a specialized region of the kidney with important homeostatic functions. It has also been implicated in genetic and developmental disorders and ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medullas baseline gene expression and epigenomic signatures have not been well described in the adult human kidney. Here we generate and analyze gene expression (RNA-seq), chromatin accessibility (ATAC-seq) and chromatin conformation (Hi-C) data from adult human kidney cortex and medulla. Using data from our carefully annotated specimens, we assign samples in the larger public GTEx database to cortex and medulla, thereby identifying several misassignments and extracting meaningful medullary gene expression signatures. Using integrated analysis of gene expression, chromatin accessibility and conformation profiles, we reveal insights into medulla development and function. Our datasets will also provide a valuable resource for researchers in the GWAS community for functional annotation of genetic variants.

genetics↗

bioRxiv2020

CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease.

Skeletal ciliopathies (e.g. Jeune syndrome, short rib polydactyly syndrome, Sensenbrenner syndrome) are frequently associated with cystic kidney disease and other organ manifestations, but a common molecular mechanism has remained elusive. We established two models for skeletal ciliopathies (ift80 and ift172) in Xenopus tropicalis, which exhibited severe limb deformities, polydactyly, cystic kidneys, and ciliogenesis defects, closely matching the phenotype of affected patients. Employing data-mining and an in silico screen we identified candidate genes with similar molecular properties to genetically validated skeletal ciliopathy genes. Among four genes experimentally validated, CRISPR/Cas9 targeting of ttc30a replicated all aspects of the phenotypes observed in the models of genetically confirmed disease genes, including ciliary defects, limb deformations and cystic kidney disease. Our findings establish three new models for skeletal ciliopathies (ift80, ift172, ttc30a) and identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins implicating post-translational tubulin modifications in its pathogenesis.

developmental biology↗

bioRxiv2020

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Chronic kidney disease (CKD) has a complex genetic underpinning. Genome-wide association studies (GWAS) of CKD-defining glomerular filtration rate (GFR) have identified hundreds of loci, but prioritization of variants and genes is challenging. To expand and refine GWAS discovery, we meta-analyzed GWAS data for creatinine-based estimated GFR (eGFRcrea) from the Chronic Kidney Disease Genetics Consortium (CKDGen, n=765,348, trans-ethnic) and UK Biobank (UKB, n=436,581, Europeans). The results (i) extend the number of eGFRcrea loci (424 loci; 201 novel; 8.9% eGFRcrea variance explained by 634 independent signals); (ii) improve fine-mapping resolution (138 99% credible sets with [≤]5 variants, 44 single-variant sets); (iii) ascertain likely kidney function relevance for 343 loci (consistent association with alternative biomarkers); and (iv) highlight 34 genes with strong evidence by a systematic Gene PrioritiSation (GPS). We provide a sortable, searchable and customizable GPS tool to navigate through the in silico functional evidence and select relevant targets for functional investigations.

genetics↗