Biology subjects

Altamirano-Pacheco, L.

Publications and source records attributed to Altamirano-Pacheco, L..

4 recordsLinked to original sources

bioRxiv2026

The mammalian genome is punctuated by regularly spaced nucleosome islands

Nucleosome positioning plays a fundamental role in regulating DNA accessibility and cellular activity, yet the precise rules by which mammalian sequences instruct this organization have remained incomplete. Prior work has established that intrinsic sequence preferences dictate nucleosome architecture in yeast, but in mammals, this sequence code is modulated by chromatin state and cell-type-specific factors. Here, we train a deep-learning model on genome-wide maps from mouse embryonic stem cells to predict nucleosome occupancy directly from the primary DNA sequence. Our model accurately predicts in vivo occupancy and captures shared biological signals while effectively denoising assay-specific technical biases. Through in silico mutagenesis, we identify specific nucleosome positioning regions comprised of short 5-to-20-base-pair motifs concentrated within dense regulatory windows. Furthermore, we demonstrate that repetitive DNA elements play a major role in establishing these highly organized nucleosome arrays on a genomic scale. Specifically, CCCTC-binding factor motifs embedded within short interspersed nuclear elements, zinc-finger-bound motifs within long interspersed nuclear elements, and microsatellite repeats act as potent organizers of nucleosome phasing. Together, our findings extend the concept of sequence-encoded nucleosome architecture to mammalian genomes and reveal that regularly spaced nucleosome islands are shaped by short, recurrent sets of DNA motifs that couple local sequence to chromatin structure.

genomics↗

bioRxiv2026

Topological Regulation of the Mammalian Genome by Positive DNA Supercoiling

DNA supercoiling is a fundamental aspect of genome topology characterizing all DNA transactions. While negative supercoiling has been extensively characterized, positive supercoiling remains poorly understood. Using a quantitative GapR profiling system, we establish comprehensive maps of positive supercoiling across interphase and mitosis. We show that positive super-coils accumulate not only at gene ends but prominently at promoters, enhancers, insulators and loop anchors, where they are resolved by Topoisomerases. Biochemical and functional assays reveal the main sources of positive torsion: transcription generates genic supercoils, while R-loops and Cohesin drive accumulation at regulatory elements, topologically associating domains and their boundaries. During mitotic chromosomal compaction, Condensins establish a global wave of positive supercoiling that largely homogenizes the genome, yet promoters with rapid post-mitotic reactivation retain elevated torsion and R-loops. These findings establish positive DNA supercoiling as a form of topological memory that links DNA mechanics to transcriptional control, genome architecture and epigenetic inheritance.

molecular biology↗

bioRxiv2023

MYC and MAX drive the reactivation of the genome after mitosis

Shortly after cell division, a robust wave of hyper-transcription reactivates the genome1-3. This phenomenon is particularly pronounced in pluripotent cells4, which necessitate rapid transcrip-tome reactivation to maintain their undifferentiated state and prevent premature differentiation. While recent work has illuminated how specific groups of genes are reactivated4-8, the mechanisms enabling the global, efficient and accurate post-mitotic reactivation of the genome remain unknown. Here we elucidate the direct involvement of the MYC/MAX transcription factors in the post-mitotic reactivation of pluripotent mouse embryonic stem cells. While MYC undergoes extensive phosphorylation and largely dissociates from its DNA binding sites during mitosis, we report that MAX remains bound to its targets, preferentially at promoters, and facilitates early recruitment of MYC following mitosis. Through the application of MYC/MAX heterodimerization inhibitors, we demonstrate their indispensable role in sustaining hyper-transcription in ES cells, including during the critical transition from mitosis to G1 phase. Our findings uncover a novel role for MAX in mitotic book-marking, highlighting its pivotal role in post-mitotic MYC recruitment and the re-establishment of high global transcription levels. These findings hold significant implications for medically relevant contexts, particularly when cell proliferation is of paramount importance9. We anticipate that the study of mitotic bookmarking by MYC and MAX and of the effects of anticancer drugs targeting MYC/MAX interactions in such process10-12 will be relevant for our understanding of cancer and its potential treatments.

molecular biology↗

bioRxiv2018

Limits to a classic paradigm: Most transcription factors regulate genes in multiple biological processes

Transcription factors (TFs) are important drivers of cellular decision-making. When bacteria encounter a change in the environment, transcription factors alter the expression of a defined set of genes in order to adequately respond. It is commonly assumed that genes regulated by the same TF should be involved in the same biological process. Examples of this are methods that rely on coregulation to infer function of not yet annotated genes. We have previously shown that only 21% of TFs regulate functionally homogeneous genes based on the proximity of their catalyzed reactions in the metabolic network. Here, we provide more evidence to support the claim that a one TF/one process relationship is not a general property. We show that the observed functional heterogeneity of regulons is not a result of the quality of the annotation of regulatory interactions, or the absence of protein-metabolite interactions, and is also present when function is defined by Gene Ontology terms. Furthermore, the observed functional heterogeneity is different from the one expected by chance, supporting the notion that it is a biological property. To further explore the relationship between transcriptional regulation and metabolism, we analyze 5 other types of regulatory groups and identify complex regulons (i.e. genes regulated by the same combination of TFs) as the most functionally homogeneous, which is supported by coexpression data. Whether higher levels of related functions exist beyond metabolism and current functional annotations, remains an open question.

bioinformatics↗