Biology subjects

Brandao, A. S.

Publications and source records attributed to Brandao, A. S..

4 recordsLinked to original sources

bioRxiv2024

Metabolic reprogramming regulates histone lactylation during zebrafish caudal fin regeneration

Tissue regeneration relies on precise molecular mechanisms controlling cell fate transitions, with cell metabolism emerging as a key regulator. Lactate-derived histone lactylation has recently been identified as an important epigenetic modification involved in the regulation of gene expression across various biological processes. In this study, we report an increase in global histone lactylation and H3K18Lac levels in the mesenchyme and osteoblasts of the zebrafish caudal fin, during the early stages of regeneration. Our findings demonstrate that this epigenetic modification is functionally regulated by increased lactate levels, while inhibition of glycolysis and lactate production significantly reduces histone lactylation. These results suggest that metabolic reprogramming, in response to caudal fin injury, regulates histone lactylation, potentially modulating gene expression essential for cell plasticity and proliferation. This study expands our understanding of how metabolic-epigenetic interactions influence regenerative processes, providing valuable insights for the development of novel therapeutic strategies to enhance tissue repair. Summary statementLactate-derived histone lactylation plays a role in the early stages of zebrafish caudal fin regeneration, coupling metabolic adaptation with tissue repair mechanisms, through epigenetic regulation.

developmental biology↗

bioRxiv2022

Fin ray branching is defined by TRAP+ osteolytic tubules

The shaping of bone structures relies on various cell types and signalling pathways. Here, we use the zebrafish bifurcating fin rays during regeneration to investigate bone patterning. We found that the regenerating fin rays form via two mineralization fronts that undergo an osteoblast-dependent fusion/stitching until the branchpoint, and that bifurcation is not simply the splitting of one unit into two. We identified tartrate-resistant acid phosphatase-positive (TRAP+) osteolytic tubular structures at the branchpoints, here named osteolytic tubules (OLTs). Chemical inhibition of their bone-resorbing activity strongly impairs ray bifurcation, indicating that OLTs counteract the stitching process. Finally, by testing different osteoactive compounds, we show that the position of the branchpoint depends on the balance between bone mineralization and resorption activities. Overall, these findings provide a new perspective on fin ray formation and bifurcation, and reveal a key role for OLTs in defining the proximo-distal position of the branchpoint. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/491182v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@7d0b9dorg.highwire.dtl.DTLVardef@1859078org.highwire.dtl.DTLVardef@1cfb816org.highwire.dtl.DTLVardef@3ec7f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Zebrafish caudal fin amputation induces a metabolic switch necessary for cell identity transitions and cell cycle re-entry to support blastema formation and bone regeneration

Regeneration depends on the ability of mature cells at the injury site to respond to injury, generating tissue-specific progenitors that incorporate the blastema and proliferate to reconstitute the original organ architecture. The metabolic microenvironment has been tightly connected to cell function and identity during development and tumorigenesis. Yet, the link between metabolism and cell identity at the mechanistic level in a regenerative context remains unclear. The adult zebrafish caudal fin, and bone cells specifically, have been crucial for the understanding of mature cell contribution to tissue regeneration. Here, we use this model to explore the relevance of glucose metabolism for the cell fate transitions preceding new osteoblast formation and blastema assembly. We show that injury triggers a shift in the metabolic profile at early stages of regeneration, enhancing glycolysis at the expense of mitochondrial oxidation. This metabolic switch mediates transcriptional changes that make mature osteoblast amenable to be reprogramed into pre-osteoblasts and induces cell cycle re-entry and progression. Manipulation of the metabolic profile led to severe reduction of the pre-osteoblast pool, diminishing their capacity to generate new osteoblasts, and to a complete abrogation of blastema formation. Overall, our data indicate that metabolic alterations have a powerful instructive role in regulating genetic programs that dictate fate decisions and stimulate proliferation, thereby providing a deeper understanding on the mechanisms regulating blastema formation and bone regeneration.

developmental biology↗

bioRxiv2021

RNA nucleotide repeats induce mitochondrial dysfunction and the ribosome associated quality control

Nucleotide repeat sequences are prevalent in the genome and expansion of these sequences is associated with more than 40 neuromuscular disorders. To understand the pathogenic mechanisms underlying RNA-repeat toxicity, we performed a genetic screen in a Caenorhabditis elegans model expressing an expanded CUG repeat specifically in the muscle. Here, we show that expression of this RNA repeat impairs motility by mitochondrial dysfunction, disrupting mitochondrial morphology and respiration. The phenotype is dependent on the RNA-binding factor MBL-1 and requires factors from the ribosome-associated protein quality control complex. Furthermore, Coenzyme Q supplementation rescued the motility impairment and all of the mitochondrial phenotypes. Together, our data reveal the importance of mitochondrial dysfunction in the molecular pathogenesis of RNA repeat expansion disorders.

genetics↗