Biology subjects

Nardocci, G.

Publications and source records attributed to Nardocci, G..

4 recordsLinked to original sources

bioRxiv2025

Increased MALAT1 Levels in Thyroid Cancer are Linked to Metabolic Reprogramming and Lymphatic Infiltration in Chilean population

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) implicated in cancer progression. In thyroid cancer, MALAT1 has been proposed as a potential biomarker, but its role in disease progression remains incompletely understood. Here, we analyzed MALAT1 RNA levels in paired tumoral and adjacent non-tumoral thyroid samples from a Chilean patient cohort. We found a positive correlation of MALAT1 levels with lymphatic infiltration that was not replicated when modeling MALAT1 expression in a larger cohort obtained from the TCGA-THCA database. An exploratory RNA-seq comparison of one matched tumor-adjacent tissue pair confirmed higher tumor abundance of MALAT1 and the epithelial-to-mesenchymal transition-marker VIM, together with lower abundance of cell-adhesion gene PCDH10. To investigate the impact of MALAT1 on thyroid cancer and cellular metabolism, we targeted MALAT1 in the papillary thyroid cancer cell line TPC1. MALAT1 knock-down reduced proliferation and migration while enhancing mitochondrial respiration with no changes in glycolysis. Notably, although MALAT1 was not localized within mitochondria, its silencing modulated the expression of transcripts associated with mitochondrial dynamics and mitophagy. Consistent with these results, transcriptomic correlation analysis in the TCGA-THCA cohort showed that MALAT1 expression was largely uncoupled from oxidative phosphorylation and glycolysis gene programs, while negatively correlating with core regulators of mitophagy and mitochondrial dynamics, pointing to a link with mitochondrial quality control rather than direct bioenergetic reprogramming. Our findings highlight MALAT1 as a contributor to thyroid cancer aggressiveness and reveal a link between MALAT1 and mitochondrial quality control independent of direct mitochondrial localization. Besides, our results support a tissue-specific mechanism and population-specific role of MALAT1 in cancer biology.

cancer biology↗

bioRxiv2022

HMGN5, an RNA or Nucleosome binding protein - potentially switching between the substrates to regulate gene expression

The packaging of DNA into chromatin and its compaction within cells renders the underlying DNA template un-accessible for processes like transcription, replication and repair. Active mechanisms as chromatin modifying activities or the association with non-coding RNAs can de-condense chromatin, rendering it accessible for the DNA dependent processes. High mobility group proteins (HMG) are small architectural chromatin proteins that were shown to contribute to the regulation of chromatin accessibility and condensation. Here we show that HMGN5, a member of the HMGN family that is capable to de-compact chromatin exhibits a novel RNA binding domain that overlaps with its nucleosome binding domain (NBD). HMGN5 binds exclusively to nucleosomes or RNA, suggesting that molecular function relies on switching between these two substrates. We show the specific binding of HMGN5 to regulatory regions and at the same time to bind the RNA of the genes it tends to activate. Furthermore, HMGN5 co-localizes and directly interacts with CTCF, suggesting a cooperative role of both proteins in organizing higher order structures of chromatin and active chromatin domains.

molecular biology↗

bioRxiv2020

A RNF12-USP26 amplification loop promotes germ cell specification and is disrupted in urogenital disorders

Ubiquitylation regulates all aspects of development, and components are frequently mutated in developmental disorders. Tonne-Kalscheuer Syndrome (TOKAS) is a X-linked multiple congenital anomaly disorder caused by mutations in the E3 ubiquitin ligase RNF12/RLIM and characterized by intellectual disability and urogenital abnormalities. However, the molecular underpinnings of TOKAS remain largely unknown. Here, we show that RNF12 catalytic activity relieves gene repression to drive a transcriptional program required for germ cell development and priming of pluripotent cells towards the germline. A major feature of the RNF12-dependent gametogenesis gene program is a transcriptional feed-forward loop featuring the deubiquitylase Usp26/USP26. Usp26/USP26 induction stabilises RNF12 to amplify transcriptional responses, which is disrupted by RNF12 TOKAS mutations and USP26 variants identified in patients with fertility defects. In summary, we uncover remarkable synergy within a ubiquitylation cycle that controls expression of key genes required for germ cell development and is disrupted in patients with urogenital abnormalities.

developmental biology↗

bioRxiv2020

Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

Conserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. Ser-Arg Repeat Protein Kinase (SRPK) is one such conserved eukaryotic kinase, which controls mRNA splicing. Surprisingly, we show that SRPK has acquired a novel function in regulating a neurodevelopmental ubiquitin signalling pathway. In mammalian embryonic stem cells, SRPK phosphorylates Ser-Arg motifs in RNF12/RLIM, a key developmental E3 ubiquitin ligase that is mutated in an intellectual disability syndrome. Processive phosphorylation by SRPK stimulates RNF12-dependent ubiquitylation of transcription factor substrates, thereby acting to restrain a neural gene expression programme that is aberrantly expressed in intellectual disability. SRPK family genes are also mutated in intellectual disability disorders, and patient-derived SRPK point mutations impair RNF12 phosphorylation. Our data reveal unappreciated functional diversification of SRPK to regulate ubiquitin signalling that ensures correct regulation of neurodevelopmental gene expression.

developmental biology↗