Biology subjects

Gallego, A.

Publications and source records attributed to Gallego, A..

3 recordsLinked to original sources

bioRxiv2026

DNA replication is dispensable for developmental progression, but required for heterochromatin organization at mouse zygotic genome activation

Early mammalian development progresses through a small number of cleavage divisions with extensive transcriptional and epigenetic reprogramming that result in the very first lineage decisions, leading to blastocyst formation. Although classical embryological studies suggested that developmental progression can occur independently of normal cell division, the extent to which DNA replication contributes to these processes remains unclear. In particular, whether replication is required simply for proliferation or also for establishing the cellular states that regulate stage-specific gene expression is unknown. Here we show that mouse preimplantation development can proceed without DNA replication, but it is required to maintain proper heterochromatin organization at the 2-cell stage, the time of zygotic genome activation. The inhibition of DNA replication with aphidicolin blocked cleavage divisions without preventing zygotic genome activation, embryo morphogenesis, activation of lineage-specification factors, or the establishment of stage-specific transcriptional programs. However, replication arrest selectively altered the expression of developmental genes associated with late-replicating, Polycomb-enriched chromatin domains, and also reduced global levels of H3K27me3 and H3K9me3. These findings indicate that developmental timing in the early embryo is largely uncoupled from DNA replication and cell-cycle progression. Instead, DNA replication contributes to transcriptional fidelity by establishing or maintaining repressive chromatin states during the extensive genome reprogramming that accompanies zygotic genome activation.

developmental biology↗

bioRxiv2025

Slow RNAPII elongation enhances naive-pluripotency rewiring while preserving replication fork speed

DNA replication and transcription must be intricately coordinated, as both machineries navigate the same chromatin landscape to ensure genome stability and proper cell function. Here, we uncover that a global imbalance between their elongation rates-- specifically, slowed transcriptional elongation alongside rapid replication fork progression--does not elicit replicative stress. Instead, this uncoupling accelerates the acquisition of naive pluripotency during in vitro de-differentiation, revealing an unexpected link between transcription kinetics and cell plasticity. Mechanistically, we show that the transition to naive pluripotency is accompanied by a distinctive alternative splicing program indicative of reduced RNAPII elongation, both in vitro and in vivo. These findings redefine the functional relationship between replication and transcription dynamics and uncover transcriptional velocity as a tunable layer of control over cellular identity transitions. HighlightsO_LIReplication and transcription elongation rates can be uncoupled genome-wide. C_LIO_LISlow transcription elongation accelerates the acquisition of naive pluripotency during in vitro de-differentiation. C_LIO_LIHigh replication fork speed is maintained in slow-transcribing cells during cell state transitions. C_LIO_LIAlternative splicing is distinctly regulated at the naive and primed pluripotency states, both in vitro and in vivo. C_LI

molecular biology↗

bioRxiv2021

Signatures of genetic variation in human microRNAs point to processes of positive selection related to population-specific disease risks

The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last twenty years. Most of them have been dedicated to study the role of specific mutations in diseases, like cancer, while a minor fraction seek to analyse the diversity profiles of microRNAs in the genomes of human populations. In the present study we analyse the latest human microRNA annotations in the light of the most updated catalog of genetic variation provided by the 1000 Genomes Project. We show by means of the in silico analysis of noncoding variation of microRNAs that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or the genomic location where they emerged. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants implicated in gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their SNPs in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.

evolutionary biology↗