Biology subjects

Chaudhri, V. K.

Publications and source records attributed to Chaudhri, V. K..

2 recordsLinked to original sources

bioRxiv2021

Diverse digital and fuzzy composite transcriptional elements are prevalent features of mammalian cis-regulomes

Mammalian transcriptional regulatory sequences are comprised of complex combinations of simple transcription factor (TF) motifs. Stereospecific juxta-positioning of simple TF motifs generates composite elements (CEs), that increase combinatorial and regulatory specificity of TF-DNA interactions. Although a small number of CEs and their cooperative or anti-cooperative modes of TF binding have been thoroughly characterized, a systematic analysis of CE diversity, prevalence and properties in cis-regulomes has not been undertaken. We developed a computational pipeline termed CEseek to discover >20,000 CEs in open chromatin regions of diverse immune cells and validated many using CAP-SELEX, ChIP-Seq and STARR-seq datasets. Strikingly, the CEs manifested a bimodal distribution of configurations, termed digital and fuzzy, based on their stringent or relaxed stereospecific constraints, respectively. Digital CEs mediate cooperative as well as anti-cooperative binding of structurally diverse TFs that likely reflect AND/OR genomic logic gates. In contrast, fuzzy CEs encompass a less diverse set of TF motif pairs that are selectively enriched in p300 associated, multi-genic enhancers. The annotated CEs greatly expand the regulatory DNA motif lexicon and the universe of TF-TF interactions that underlie combinatorial logic of gene regulation.

genomics↗

bioRxiv2020

Alveolar early progenitors in the aged human lung have increased expression of ACE2 accompanied with genes involved in beta-amyloid clearance: Indication of SARS-CoV-2 also using soluble ACE2 in aged-lungs to enter ACE2-negative cells

COVID-19 is the current pandemic caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2) that uses ACE2 protein on the cell surface. By analyzing publicly available datasets, I uncovered that alveolar early progenitors (AEP), a subset of the type-2 pneumocytes, showed increased ACE2 expression in the older lungs. AEPs co-express TMPRSS2, CTSL. Aged AEP-gene expression signature suggested an active response to beta-amyloid-induced ACE2 shedding, to limit the intercellular beta-amyloid accumulation in otherwise healthy human lungs. Susceptibility of AEP to SARS-CoV2 and ACE2 secretory capacity of these cells makes aged human lung sensitive for rapid-infection, by a possible in-solution ACE2 binding and entry into ACE2-negative cells, thereby increasing the target cell diversity and numbers. Single-cell analysis of COVID19 patients with moderate and severe infections, clearly showed that severe infections showed SARS-CoV-2 transcript in ACE2-negative TMPRSS-negative but CTSL-positive cell types in their bronchoalveolar lavage fluid, validating in-solution ACE2-binding enabling infection.

systems biology↗