Biology subjects

Paz, M. A.

Publications and source records attributed to Paz, M. A..

4 recordsLinked to original sources

bioRxiv2026

Multilayered specificity of transcription factor binding at cytokine promoters

Transcription factors (TFs) regulate gene expression through sequence-specific DNA binding, and their genomic occupancy is further influenced by TF expression, activation state, and protein-protein interactions. How these mechanisms determine context-specific gene regulation remains incompletely understood, particularly for tightly controlled immune genes such as cytokines. Here, we use paired yeast one-hybrid (pY1H) assays to systematically examine DNA binding of 236 TFs and 392 TF-pairs across 106 cytokine gene promoters. Of the 1,619 TF-promoter interactions identified, 555 required TF cooperativity and 410 were antagonized by at least one TF partner, suggesting that TF-DNA binding is highly dependent on TF partners. Usage of different partners can drastically alter a TFs target repertoire and may result in the recruitment of different transcriptional cofactors. Integration with existing data on TF expression and activation further showed that cooperativity and antagonism provide additional, underappreciated layers of DNA-binding specificity.

systems biology↗

bioRxiv2026

Atlas of HIV cis-regulatory elements reveals extensive transcriptional variation across clades, isolates, and within individuals

Human immunodeficiency virus (HIV) replication, persistence, and reactivation depend on transcription from integrated proviruses. Despite extensive sequence variation, how viral genetic diversity influences transcriptional regulation remains poorly understood. Here, we generate a functional regulatory atlas of HIV-1 and HIV-2 by combining tiling and saturation mutagenesis massively parallel reporter assays (MPRAs) with comparative sequence analysis and predictive modeling. By profiling thousands of HIV isolates in Jurkat and human primary CD4+T cells, we reveal extensive variation in baseline and stimulus-induced long terminal repeat (LTR) activity across and within clades, driven by distinct transcription factor configurations. These activities frequently differ among proviruses from the same individual and shift over infection and transmission without consistent selection for activity. Beyond the LTR, we identify conserved intragenic cis-regulatory elements, revealing regulatory architectures that complement LTR activity. Finally, we develop sequence-based models that accurately predict transcriptional activity, enabling scalable functional annotation of viral diversity and evolution.

microbiology↗

bioRxiv2025

Global cis-regulatory landscape of double-stranded DNA viruses

Most double-stranded DNA (dsDNA) viruses use the host transcriptional machinery to express viral genes for replication and immune evasion. This is mediated by viral cis-regulatory elements (CREs) regulated by host and viral transcription factors (TFs). Although some viral CREs and their regulatory mechanisms have been determined, most remain unidentified. Here, we used massively parallel reporter assays to identify [~]2,000 CREs across 27 dsDNA viruses from the Adenovirus, Herpesvirus, Polyomavirus and Papillomavirus families. Viral genomes have a higher CRE density than the human genome, with most viral CREs having promoter-like features and overlapping protein coding sequences. Using saturation mutagenesis and machine learning models, we report viral CRE regulators, including SP, ETS, bZIPs, and TFs acting downstream of signal-activated pathways. Altogether, we present a comprehensive functional CRE map of human-infecting dsDNA viruses that serves as a blueprint for further studies in viral regulation, reactivation, evolution, and viral vector design.

genomics↗

bioRxiv2020

KIR2DL4 genetic diversity in a Brazilian population sample: implications for transcription regulation and protein diversity in samples with different ancestry backgrounds

KIR2DL4 is an important immune modulator expressed in Natural Killer cells, being HLA-G its main ligand. We characterize KIR2DL4 gene diversity considering the promoter, all exons, and all introns, in a highly admixed Brazilian population sample using massively parallel sequencing. We also introduce a molecular method to amplify and sequence the complete KIR2DL4 gene. To avoid mapping bias and genotype errors commonly observed in gene families, we have developed a bioinformatic pipeline designed to minimize mapping, genotyping, and haplotyping errors. We have applied this method to survey the variability of 220 samples from the State of Sao Paulo, southeastern Brazil. We have also compared the KIR2DL4 genetic diversity in Brazilian samples with the previously reported by the 1000Genomes consortium. KIR2DL4 presents high linkage disequilibrium throughout the gene, with coding sequences associated with specific promoters. There were few, but divergent, promoter haplotypes. We have also detected many new KIR2DL4 sequences, all with nucleotide exchanges in introns and encoding previously described proteins. Exons 3 and 4, which encode the external domains, were the most variable ones. The ancestry background influences KIR2DL4 allele frequencies and must be considered for association studies regarding KIR2DL4.

genetics↗