Biology subjects

Mir, H.

Publications and source records attributed to Mir, H..

4 recordsLinked to original sources

bioRxiv2025

Allosteric inhibition rescues hydrocephalus caused by catalytically inactive Shp2

SHP2, a protein tyrosine phosphatase (PTP) crucial in Ras-MAPK signaling, is associated with various human congenital diseases and cancers. Here, we show that the catalytically inactive Shp2C459S mutation results in communicating hydrocephalus, similar to the catalytically activating Shp2E76K and Mek1DD mutants. Unlike previous mutants, however, Shp2C459S/+ mutation uniquely affects ciliary development rather than neurogenesis, leading to reduced cilia density and impaired ciliary motility. Differential scanning fluorimetry revealed that SHP2C459S, SHP2E76K and SHP2C459S/E76K mutations all induce an open SHP2 conformation, but only SHP2C459S leads to aberrant GAB1 phosphorylation in cells expressing wild-type SHP2. This distinctive signaling pattern correlates with our observations in brain ventricular tissues of Shp2C459S/+ mice, where Erk and Stat3 activities remain normal but Gab1 phosphorylation is elevated. Critically, we show that the hydrocephalus phenotype in Shp2C459S mice can be mitigated by allosteric inhibition of Shp2. These findings suggest that Shp2-associated hydrocephalus is driven by conformational changes rather than altered catalytic activity. Our results underscore the therapeutic potential of conformation-specific allosteric inhibitors in targeting both catalytically active and inactive SHP2 mutants.

pathology↗

bioRxiv2024

Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice

Iron-sulfur clusters (ISCs) are cell-essential cofactors present in [~]60 proteins including subunits of OXPHOS complexes I-III, DNA polymerases, and iron-sensing proteins. Dysfunctions in ISC biosynthesis are associated with anemias, neurodegenerative disorders, and metabolic diseases. To assess consequences of acute ISC inhibition in a whole body setting, we developed a mouse model in which key ISC biosynthetic enzyme NFS1 can be acutely and reversibly suppressed. Contrary to in vitro ISC inhibition and pharmacological OXPHOS suppression, global NFS1 inhibition rapidly enhances lipid utilization and decreases adiposity without affecting caloric intake and physical activity. ISC proteins decrease, including key proteins involved in OXPHOS (SDHB), lipoic acid synthesis (LIAS), and insulin mRNA processing (CDKAL1), causing acute metabolic inflexibility. Age-related metabolic changes decelerate loss of adiposity substantially prolonged survival of mice with NFS1 inhibition. Thus, the observation that ISC metabolism impacts organismal fuel choice will aid in understanding the mechanisms underlying ISC diseases with increased risk for diabetes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/608291v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@863cbaorg.highwire.dtl.DTLVardef@fce90borg.highwire.dtl.DTLVardef@27df04org.highwire.dtl.DTLVardef@1a2a9bf_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Acute ISC inhibition leads to rapid loss of adiposity in mice - Multi-metabolic pathway disruption upon ISC deficiency blocks energy storage - Nfs1 inhibition induces glucose dyshomeostasis due to ISC deficiency in {beta}-cells - Energy distress caused by inhibition of ISC synthesis is attenuated in aged mice

physiology↗

bioRxiv2022

To make a short story long: simultaneous short and long RNA profiling on Nanopore devices

Sequencing of long coding RNAs informs about the abundance and the novelty in the transcriptome, while sequencing of short coding RNAs (e.g., microRNAs) or long non-coding RNAs informs about the epigenetic regulation of the transcriptome. Currently, each of these goals is addressed by separate sequencing experiments given the different physical characteristics of RNA species from biological samples. Sequencing of both short and long RNAs from the same experimental run has not been reported for long-read Nanopore sequencing to date and only recently has been achieved for short-read (Illumina) methods. We propose a library preparation method capable of simultaneously profiling short and long RNA reads in the same library on the Nanopore platform and provide the relevant bioinformatics workflows to support the goals of RNA quantification. Using a variety of synthetic samples we demonstrate that the proposed method can simultaneously detect short and long RNAs in a manner that is linear over 5 orders of magnitude for RNA abundance and three orders of magnitude for RNA length. In biological samples the proposed method is capable of profiling a wider variety of short and long non-coding RNAs when compared against the existing Smart-seq protocols for Illumina and Nanopore sequencing.

molecular biology↗

bioRxiv2022

Comprehensive Analysis of Regenerative and Transformed Liver Reveals Distinct, Early Metabolic Alterations in Cancer

Alterations in cellular metabolism represent an important response to proliferative signals in both normal and transformed tissues. The benign proliferative process of liver regeneration after partial hepatectomy offers insight into homeostatic mechanisms to control liver mass, which are disrupted in liver disease induced by viral factors, alcohol, or associated with obesity. Moreover, successful targeting of cancer depends on the identification of genes and pathways that are selectively activated in the transformed state. Here, we present a differential transcriptomic and metabolomic analysis of benign proliferative and transformed liver, including associated plasma metabolite and lipid species. Using partial hepatectomy-induced liver regeneration and diethylnitrosamine (DEN) induced carcinogenesis, we identify and analyze alterations specific to multiple regenerative and transformed tissue states. Transcriptomics and LC/MS based metabolite profiling reveal fatty acid import and storage are specifically rewired during liver regeneration in a time dependent manner, a phenomenon not observed in liver tumors. In contrast, liver tumors exhibit preferential activation of numerous metabolic pathways, including glycolysis, serine biosynthesis, and polyamine metabolism. Alterations in serine metabolism occur at the earliest detectable stages in tumorigenesis and promote survival upon serine restriction. These data demonstrate that transformation-induced alterations in metabolism are distinct from those observed in normal regenerative cell division, which may be used to identify transformation-specific liabilities.

cancer biology↗