Biology subjects

Hariharan, N.

Publications and source records attributed to Hariharan, N..

9 recordsLinked to original sources

bioRxiv2026

Angiogenin activity regulates RNA remodeling during the maternal-to-zygotic transition in early mouse embryogenesis

Angiogenin (ANG), a member of the RNase A superfamily, regulates multiple aspects of RNA metabolism, including rRNA processing and the generation of tRNA-derived small RNAs. However, its function during early mammalian embryogenesis remains unknown. Here, we identify a previously unrecognized requirement for ANG activity during early mouse embryonic development. Pharmacological inhibition of ANG during the first embryonic cell cycle did not prevent progression to the 2-cell stage but markedly impaired subsequent development to the 4-cell stage, indicating a critical requirement for ANG activity during the maternal-to-zygotic transition. Transcriptome-wide analysis revealed that ANG inhibition disrupted the normal remodeling of the embryonic transcriptome, characterized by persistent accumulation of a subset of transcripts that are normally reduced during the 2-cell transition, including many maternally deposited RNAs, together with altered expression of transcripts associated with zygotic genome activation. Small-RNA profiling further revealed widespread alterations in miRNA and tRNA-derived small-RNA populations. Notably, a large proportion of transcripts retained following ANG inhibition contained predicted target sites for miRNAs that were concomitantly reduced, suggesting a potential link between ANG-dependent small-RNA regulation and maternal transcript clearance. ANG inhibition was also associated with altered abundance and organization of components of RNA regulatory granules, including Tudor, TIAR, Dcp1a and Ago2, and increased association of selected retained transcripts Reep4 and Esrrb with Tudor-positive structures. Together, these findings identify ANG activity as an important regulator of RNA remodeling during the maternal-to-zygotic transition and suggest that ANG coordinates maternal transcript clearance, small-RNA dynamics and mRNP organization to support early mouse embryonic development.

developmental biology↗

bioRxiv2026

OMICON: a community resource for studying gene coexpression networks in normal and neoplastic human brain samples

Genome-wide coexpression analysis of intact tissue samples is a powerful approach for identifying reproducible signatures of cell types and states, since it can survey vast numbers of individuals, cells, and transcripts. However, it can be difficult to optimize gene coexpression network construction and compare results from independent analyses. To address these challenges, we developed OMICON (theomicon.ucsf.edu) for research on human brain gene coexpression networks. OMICON contains gene expression data from >17K normal and neoplastic human brain samples with standardized metadata. Systematic analysis of independent datasets identified >250K gene coexpression modules, which were characterized and compared via enrichment analysis with >40K gene sets. All modules are discoverable via an advanced search engine that can filter by genes, metadata, and enrichment results. Analyses can also be browsed with an interactive workflow visualization tool, and users can communicate within OMICON using @mention functionality to support communal research on human brain gene coexpression networks.

neuroscience↗

bioRxiv2026

An oxo-mechanical coupling determines cell state

Across myriad habitats and diverse lifeforms, oxygen and mechanics are the most ubiquitously varying and profoundly influential environmental regulators. While physiological niches feature both varying oxygen levels and heterogeneous mechanics, laboratory experiments typically interrogate these as independent variables. Here, we show that combinatorial regimes defined by varying oxygen partial pressures and environmental mechanics--an oxo-mechanical cue--induce functionally-distinct cellular states in 3D ECM-like contexts. Single-cell morphometrics combined with multi-omics reveal that cellular response to oxygen deprivation depends on external mechanical milieus, whereas, cellular engagement with different mechanical microenvironments depends on oxygen availability. Independently perturbing both hypoxic signaling and cytoskeletal activity further reveals a reciprocal oxo-mechanical regulatory coupling, which operates by differentially altering the global chromatin accessibility for transcriptional regulation in response to specific combinations of oxygen partial pressures and external mechanical milieus. Together, our findings establish that a coupling between oxygen and mechanics drives the emergence of microenvironmentally-defined cell states.

cell biology↗

bioRxiv2024

Altering rRNA 2'O-methylation pattern during neuronal differentiation is regulated by FMRP

The Fragile X Messenger Ribonucleoprotein (FMRP) is a selective RNA-binding protein that localizes to the cytoplasm and the nucleus. The loss of FMRP results in Fragile X Syndrome (FXS), an Autism Spectrum Disorder. FMRP interacts with ribosomes and regulates the translation of mRNAs essential for neuronal development and synaptic plasticity. However, the biochemical nature of this translation regulation is unknown. Here we report that a key feature of FMRP-mediated translation regulation during neuronal differentiation is modulating the 2O-methylation of ribosomal RNA. 2O-methylation, facilitated by C/D box snoRNAs in the nucleus, is a major epitranscriptome mark on rRNA, essential for ribosome assembly and function. We found that FMRP influences a distinct rRNA 2O-Methylation pattern across neuronal differentiation. We show that in H9 ESCs, FMRP interacts with a selected set of C/D box snoRNA in the nucleus resulting in the generation of ribosomes with a distinct pattern of rRNA 2O-Methylation. This epitranscriptome pattern on rRNA undergoes a significant change during the differentiation of ESCs to neuronal precursors and cortical neurons. ESCs display maximum hypomethylated residues on rRNA, which is eventually reduced in neuronal precursors and post-mitotic cortical neurons and this is correlated to the change in global protein synthesis among the states of differentiation. Importantly, this gradual change in the 2O-methylation pattern during neuronal differentiation is altered in the absence of FMRP, which could impact neuronal development and contribute to dysregulated protein synthesis observed in Fragile X Syndrome. This also suggests the need for diversity in functional ribosomes during the early stages of development.

molecular biology↗

bioRxiv2024

Dietary stress induced macrophage metabolic reprogramming, a determinant of animal growth

Nutrient sensing and signaling play pivotal roles in animal growth. However, under dietary stress, this system falters, leading to growth defects. While immune cells are increasingly recognized as key nutrient sensors, their impact on animal growth remains poorly understood. In this study, we investigate how Drosophila larval macrophages respond to excessive dietary sugar and identify a reconfiguration of their metabolic state. They undergo a glycolytic shift, intensify TCA activity, and elevate TAG synthesis. While typical of sugarinduced nutrient stress, these changes interestingly exert contrasting effects on animal growth: glycolysis and increased TCA activity inhibit growth, while the lipogenic shift promotes it. However, the lipogenic response is insufficient to counteract the metabolic events suppressing growth, resulting in an overall reduction in adult fly size under high sugar conditions. Stimulating a pro-lipogenic immune state facilitates growth recovery, suggesting a growth paradigm governed by immune-metabolic transitions. This study unveils the unexpected influence of macrophage metabolic reprogramming on organismal growth homeostasis during Drosophila development, highlighting immune cell states as central determinants of growth, particularly under dietary stress.

developmental biology↗

bioRxiv2024

Poly (A) Binding Protein 2 is critical for stem-progenitor differentiation during regeneration in the planarian Schmidtea mediterranea.

Post-transcriptional regulation has emerged as a key mechanism to regulate stem cell renewal and differentiation, which is essential for understanding tissue regeneration and homeostasis. Poly(A)-binding proteins are a family of RNA-binding proteins that play a vital role in post-transcriptional regulation by controlling mRNA stability and protein synthesis. The involvement of poly(A) binding proteins in a wide range of cellular functions is increasingly being investigated. In this study, we used the regenerative model organism planarian Schmidtea mediterranea, to demonstrate the critical role of poly(A)-binding protein 2 (PABP2) in regulating neoblast maintenance and differentiation. A deficit in PABP2 blocks the transition of neoblasts towards immediate early progenitors, leading to an enhanced pool of non-committed neoblasts and a decreased progenitor population. This is reflected in variations in the transcriptome profile, providing evidence of downregulation in multiple lineages. Thus, insufficiency of PABP2 resulted in defective formation and organization of tissue leading to abnormal regeneration. Our study reveals the essential role of PABP2 in regulating genes that mediate stem cell commitment to early progenitors during tissue regeneration.

cell biology↗

bioRxiv2022

ES30L: A large subunit rRNA expansion segment enriched in mammals and birds

Ribosomes, the molecular machines that are central to protein synthesis, have gradually been gaining prominence for their regulatory role in translation. Eukaryotic cytosolic ribosomes are typically larger than bacterial ones, partly due to multi-nucleotide insertions at specific conserved positions in the ribosomal RNAs (rRNAs). Such insertions called expansion segments (ESs) are present primarily on the ribosomal surface, with their role in translation and its regulation remaining under-explored. One such ES in the ribosomal large subunit (LSU) is ES30L, which is present only in mammals and birds among eukaryotes. In this study, we show that ES30L possesses complementarity to many protein-coding transcripts in humans and that the complementarity is enriched around the start codon, hinting at a possible role in translation regulation. Further, our in silico analysis analyses and pull-down assays indicate that ES30L may bind to secondary structures in the 5 UTR of several transcripts and RNA binding proteins (RBPs) that are essential for translation. Thus, we have identified a potential regulatory role for ES30L in translation.

molecular biology↗

bioRxiv2022

Novel cell- and stage-specific transcriptional signatures defining Drosophila neurons, glia and hemocytes

Cell types can be now defined at unprecedented resolution using high throughput assays. We analyzed the transcriptional signatures of Drosophila neurons, glia and hemocytes, as examples of cell types that are related by position (glia/neurons) or function (glia/hemocytes) or that are unrelated (neurons/hemocytes). The most related cells display the highest similarity level (neurons and glia), the least related ones, the lowest (neurons and hemocytes), however, cells can show plastic features. Glia are much more similar to neurons than to hemocytes in the embryo, but are equally similar to the two cell types in the larva, when hemocytes acquire more immune functions. Larval glia and hemocytes display common as well as specific immune features, such as the glia-specific NimA receptor, in agreement with the different environment faced by each cell types. Surprisingly, time represents a key identity parameter, as neurons, hemocytes and glia group more significantly by the stage than by the cell type and larval cells show upregulation of genes involved in chromatin organization and in DNA repair. This latter group of genes is linked to changes in gene expression levels and chromatin organization, revealing a function of these genes beyond DNA repair. Finally, the metabolic profiles reveal cell type-specific signatures and an overall shift from an embryonic, anabolic state to a larval, catabolic state.

developmental biology↗

bioRxiv2019

Temporal specificity and heterogeneity of the fly immune cells' transcriptional landscape

Immune cells provide defense against the non-self, however recent data suggest roles well beyond innate immunity, in processes as diverse as development, metabolism and tumor progression. Nevertheless, the heterogeneity of these cells remains an open question. Using bulk RNA sequencing we find that the Drosophila immune cells (hemocytes) display distinct features in the embryo, a closed and rapidly developing system, compared to the larva, which is exposed to environmental and metabolic challenges. Through single cell RNA sequencing we identify fourteen hemocyte clusters present in unchallenged larvae and associated with distinct cellular processes e.g. proliferation, phagocytosis, metabolic homeostasis and humoral response. Finally, we characterize the changes occurring in the hemocyte clusters upon wasp infestation that triggers the differentiation of a novel cell type, the lamellocyte. This first molecular atlas provides precious insights and paves the way to study the biology of the Drosophila immune cells in physiological and pathological conditions.

developmental biology↗