Biology subjects

da Rocha, E. L.

Publications and source records attributed to da Rocha, E. L..

3 recordsLinked to original sources

bioRxiv2025

Dynamic activity of Erg promotes aging of the hematopoietic system

Hematopoiesis changes to adapt to the physiology of development and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts over the lifespan is unknown. Here, we show that expression of the ETS family TF Erg is adult-biased, and that programmed upregulation of Erg expression during juvenile to adult aging is evolutionarily conserved and required for complete implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs, and persistent juvenile phenotypes in Erg haploinsufficient mice are dependent on deregulation of the fetal-biased TF Hmga2. Finally, Erg haploinsufficiency in the adult results in fetal-like resistance to leukemogenesis. Overall, we identify a mechanism whereby HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases. SUMMARYThe hematopoietic system undergoes a process of coordinated aging from the juvenile to adult states. Here, we find that expression of ETS family transcription factor Erg is temporally regulated. Impaired upregulation of Erg during the hematopoietic maturation results in persistence of juvenile phenotypes.

developmental biology↗

bioRxiv2025

LIN28-mediated gene regulatory loops synchronize developmental transitions throughout organogenesis

Precise control of the intervals between self-renewal, proliferation, and differentiation of stem/progenitor cells are coordinated by developmental regulators, comprised of both microRNAs (miRNAs) and proteins, termed heterochronic genes. These heterochronic factors make up a unique subset of evolutionarily conserved genes that regulate the developmental rate and timing of metazoans from worms to mammals. We and others have shown critical roles for the RNA-binding proteins (RBPs) Lin28 during pluripotency, reprogramming, and organogenesis. There has been much investigation into the negative feedback loop between the Lin28-RBPs and the miRNAs-Let-7 during development and disease. Albeit there are fewer investigations into how positive feedback loops between mammalian Lin28-RBPs and mRNAs order mammalian spatiotemporal transitions of progenitors from specification to organogenesis. Screening for factors that activate luciferase reporters of the human LIN28A and LIN28B promoters, in combination with genetic mouse models, we demonstrate positive feedforward loops between key developmental transcription factors such as B-Catenin, Sox2, Sox9, and Lin28-RBPs. Furthermore, we demonstrate heterochronic regulation of morphogenesis and ultimately differentiation is not only genetically moderated but also molecularly fine-tuned via position-dependent sequences in the 5 and/or 3 untranslated regions.

developmental biology↗

bioRxiv2019

Flaviviruses exploit fine-tuning of the interferon response to promote replication

The establishment of a virus infection is the result of the pathogens ability to replicate in a hostile environment generated by the hosts immune system. Here, we found that ISG15 restricts Dengue and Zika viruses replication through the stabilisation of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signalling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2s stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing hosts IFN-I mediated response and promoting virus replication. IMPORTANCEDisease is an emergent property that results from a microorganisms ability to replicate in a given host and the latters immune response. Here we describe how the immunoregulatory function of ISG15 (an interferon stimulated gene) affects Dengue and Zika virus replication by occupying a niche used by the virus non-structural protein 5 (NS5) to evade hosts immunity. In the absence of ISG15, NS5 efficiently degrades a main signalling hub of innate immunity (STAT2), leading to cell immune suppression and consequently virus growth. This sheds light into how flaviviruses intimately interact with the host immune system and could lead to a host-based therapy target.

immunology↗