Biology subjects

Lindeboom, R. G.

Publications and source records attributed to Lindeboom, R. G..

2 recordsLinked to original sources

bioRxiv2023

The emergence of goblet inflammatory or ITGB6hi nasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis

Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30- 50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hi progenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/524211v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@dab12aorg.highwire.dtl.DTLVardef@1a57334org.highwire.dtl.DTLVardef@12e7983org.highwire.dtl.DTLVardef@2bbe6e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Chromatin regulates genome-wide transcription factor binding affinities

Transcription factor binding across the genome is regulated by DNA sequence and chromatin features. However, it is not yet possible to quantify the impact of chromatin context on genome-wide transcription factor binding affinities. Here we report the establishment of a method to determine genome-wide absolute apparent binding affinities of transcription factors to native, chromatinized DNA. Our experiments revealed that DNA accessibility is the main determinant of transcription factor binding in the genome, which largely restricts nanomolar affinity binding of YY1, SP1 and MYC/MAX to promoters, while FOXA1 also interacts with non-promoter elements with high affinity. Furthermore, whereas consensus DNA binding motifs for transcription factors are important to establish very high-affinity binding sites, these motifs are not always strictly required to generate nanomolar affinity interactions in the genome. Finally, we uncovered transcription factor concentration dependent binding to specific gene classes, suggesting transcription factor concentration dependent effects on gene expression and cell fate. Importantly, our method adds a quantitative dimension to transcription factor biology which enables stratification of genomic targets based on transcription factor concentration and prediction of transcription factor binding sites under non-physiological conditions, such as disease associated overexpression of (onco)genes.

genomics↗