Biology subjects

Arif, A.

Publications and source records attributed to Arif, A..

5 recordsLinked to original sources

bioRxiv2022

Relaxed targeting rules allow PIWI-clade Argonaute proteins to silence ever-mutating transposons

In animals, piRNAs direct PIWI-clade Argonaute proteins to slice complementary transposon transcripts. Transposons can evade silencing through target site mutations. We report that PIWIs efficiently cleave transcripts only partially paired to their piRNA guide. Measurements of mouse PIWI protein affinity and cleavage rates for thousands of RNAs in vitro and in vivo show that PIWI slicing tolerates mismatches to any target nucleotide, including those flanking the scissile phosphate. Although piRNA 5 terminal nucleotides accelerate target finding, they are dispensable for binding or catalysis--unlike AGO-clade Argonautes, which require uninterrupted siRNA:target pairing from the seed to the nucleotides past the scissile bond. PIWIs are thus better equipped than AGOs to target newly acquired or rapidly diverging endogenous transposons without recourse to novel small RNA guides.

molecular biology↗

bioRxiv2021

TISON: a next-generation multi-scale modeling theatre for in silico systems oncology

Multi-scale models integrating biomolecular data from genetic, transcriptional, and translational levels, coupled with extracellular microenvironments can assist in decoding the complex mechanisms underlying system-level diseases such as cancer. To investigate the emergent properties and clinical translation of such cancer models, we present Theatre for in silico Systems Oncology (TISON, https://tison.lums.edu.pk), a next-generation web-based multi-scale modeling and simulation platform for in silico systems oncology. TISON provides a "zero-code" environment for multi-scale model development by seamlessly coupling scale-specific information from biomolecular networks, microenvironments, cell decision circuits, in silico cell lines, and organoid geometries. To compute the temporal evolution of multi-scale models, a simulation engine and data analysis features are also provided. Furthermore, TISON integrates patient-specific gene expression data to evaluate patient-centric models towards personalized therapeutics. Several literature-based case studies have been developed to exemplify and validate TISONs modeling and analysis capabilities. TISON provides a cutting-edge multi-scale modeling pipeline for scale-specific as well as integrative systems oncology that can assist in drug target discovery, repositioning, and development of personalized therapeutics.

systems biology↗

bioRxiv2021

The tiny, conserved zinc-finger protein GTSF1helps PIWI proteins achieve their full catalytic potential

Argonaute proteins use nucleic acid guides to find and bind specific DNA or RNA target sequences. Argonaute proteins can be found in all kingdoms of life, and play diverse biological functions including genome defense, gene regulation, and chromosome partitioning. Many Argonautes retain their ancestral endoribonuclease activity, cleaving the phosphodiester bond between target nucleotides t10 and t11. In animals, a specialized class of Argonautes, the PIWI proteins, use 21-35 nt PIWI-interacting RNAs (piRNAs) to direct transposon silencing, protect the germline genome, and regulate gene expression during gametogenesis1. The piRNA pathway is required for fertility in one or both sexes of nearly all animals. Both piRNA production and function require RNA cleavage catalyzed by PIWI proteins. Spermatogenesis in mice and other placental mammals requires three distinct, developmentally regulated PIWI proteins: MIWI (PIWIL1), MILI (PIWIL2), and MIWI2 (PIWIL4)2-4. The piRNA-guided endoribonuclease activities of MIWI and MILI are essential to produce functional sperm5, 6. piRNA-directed silencing in mice and insects also requires Gametocyte-Specific Factor 1 (GTSF1), a PIWI-associated protein of unknown function7-12. Here, we report that GTSF1 potentiates the weak, intrinsic, piRNA-directed RNA cleavage activities of PIWI proteins, transforming them into efficient endoribonucleases. GTSF1 represents the first example of an auxiliary protein that potentiates the catalytic activity of an Argonaute protein.

biochemistry↗

bioRxiv2021

The testis-specific transcription factor TCFL5 responds to A MYBto elaborate the male meiotic program in placental mammals

In male mice, the transcription factor (TF) A-MYB initiates reprogramming of gene expression after spermatogonia enter meiosis. We report that A-MYB activates Tcfl5, a testis-specific TF first produced in pachytene spermatocytes. Subsequently, A-MYB and TCFL5 reciprocally reinforce their own transcription to establish an extensive circuit that regulates meiosis. TCFL5 promotes transcription of genes required for mRNA turnover, pachytene piRNA production, meiotic exit, and spermiogenesis. This transcriptional architecture is conserved in rhesus macaque, suggesting TCFL5 plays a central role in meiosis and spermiogenesis in placental mammals. Tcfl5em1/em1 mutants are sterile, and spermatogenesis arrests at the mid- or late-pachytene stage of meiosis.

genetics↗

bioRxiv2020

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

ABSTRACTFibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established pro-inflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.Competing Interest StatementThe authors have declared no competing interest.View Full Text

molecular biology↗