Gene regulatory network inference with popInfer reveals dynamic regulation of hematopoietic stem cell quiescence upon diet restriction and aging.

Inference of gene regulatory networks (GRNs) can reveal cell state transitions from single-cell genomics data. However, obstacles to temporal inference from snapshot data are difficult to overcome. Single-nuclei multiomics data offer means to bridge this gap and derive temporal information from snapshot data using joint measurements of gene expression and chromatin accessibility in the same single cells. We developed popInfer to infer networks that characterize lineage-specific dynamic cell state transitions from joint gene expression and chromatin accessibility data. Benchmarking against alternative methods for GRN inference, we showed that popInfer achieves higher accuracy in the GRNs inferred. popInfer was applied to study single-cell multiomics data characterizing hematopoietic stem cells (HSCs) and the transition from HSC to a multipotent progenitor cell state during murine hematopoiesis across age and dietary conditions. From networks predicted by popInfer, we discovered gene interactions controlling entry to/exit from HSC quiescence that are perturbed in response to diet or aging.

Evolution, mechanism and limits of dietary restriction induced health benefits & longevity.

Dietary restriction (DR) is the most powerful intervention to enhance health and lifespan across species. However, recent findings indicate that DR started in late life has limited capacity to induce health benefits. Age-dependent changes that impair DR at old age remain to be delineated. This requires a better mechanistic understanding of the different aspects that constitute DR, how they act independently and in concert. Current research efforts aim to tackle these questions: Are fasting periods needed for the induction of DR's health benefits? Does the improvement of cellular and organismal functions depend on the reduction of specific dietary components like proteins or even micronutrients and/or vitamins? How is the aging process intervening with DR-mediated responses? Understanding the evolutionary benefits of nutrient stress responses in driving molecular and cellular adaptation in response to nutrient deprivation is likely providing answers to some of these questions. Cellular memory of early life may lead to post-reproductive distortions of gene regulatory networks and metabolic pathways that inhibit DR-induced stress responses and health benefits when the intervention is started at old age. Inhere we discuss new insights into mechanisms of DR-mediated health benefits and how evolutionary selection for fitness in early life may limit DR-mediated improvements at old age.

Loop Interrupted: Dysfunctional Chromatin Relations in Neurological Diseases.

The majority of genetic variants for psychiatric disorders have been found within non-coding genomic regions. Physical interactions of gene promoters with distant regulatory elements carrying risk alleles may explain how the latter affect gene expression. Recently, whole genome maps of long-range chromosomal contacts from human postmortem brains have been integrated with gene sequence and chromatin accessibility data to decipher disease-specific alterations in chromatin architecture. Cell culture and rodent models provide a causal link between chromatin conformation, long-range chromosomal contacts, gene expression, and disease phenotype. Here, we give an overview of the techniques used to study chromatin contacts and their limitations in brain research. We present evidence for three-dimensional genome changes in physiological brain function and assess how its disturbance contributes to psychiatric disorders. Lastly, we discuss remaining questions and future research directions with a focus on clinical applications.

Linker histone H1.5 is an underestimated factor in differentiation and carcinogenesis.

Human histone H1.5, in mice called H1b, belongs to the family of linker histones (H1), which are key players in chromatin organization. These proteins sit on top of nucleosomes, in part to stabilize them, and recruit core histone modifying enzymes. Through subtype-specific deposition patterns and numerous post-translational modifications, they fine-tune gene expression and chromatin architecture, and help to control cell fate and homeostasis. However, even though it is increasingly implicated in mammalian development, H1.5 has not received as much research attention as its relatives. Recent studies have focused on its prognostic value in cancer patients and its contribution to tumorigenesis through specific molecular mechanisms. However, many functions of H1.5 are still poorly understood. In this review, we will summarize what is currently known about H1.5 and its function in cell differentiation and carcinogenesis. We will suggest key experiments that are required to understand the molecular network, in which H1.5 is embedded. These experiments will advance our understanding of the epigenetic reprogramming occurring in developmental and carcinogenic processes.