Neuromodulators and neuroepigenetics of social behavior in ants.

Eusocial insects exemplify a remarkable system of division of labor within the same colony. This behavioral range, which is sometimes accompanied by morphological or physiological differences, provides an opportunity to study the relationship between complex behaviors and their underlying molecular mechanisms. This is especially true in ants because certain genera have an elaborate caste system and can dramatically change their stereotypical behavior over their lifetime. Recent studies experimentally alter ant behavior over short times, thus opening the study of underlying plasticity pathways. The molecular underpinnings of these behaviors are neuromodulators as well as the regulation of chromatin. Here, we concisely review the current understanding of the relationship between neuromodulators, epigenetics, and social behavior in ants. We discuss future directions in light of experimental limitations of the ant system.

Impaired activation of transposable elements in SARS-CoV-2 infection.

Emerging evidence shows that transposable elements (TEs) are induced in response to viral infections. This TE induction is suggested to trigger a robust and durable interferon response, providing a host defense mechanism. Here, we analyze TE expression changes in response to SARS-CoV-2 infection in different human cellular models. Unlike other viruses, SARS-CoV-2 infection does not lead to global upregulation of TEs in primary cells. We report a correlation between TEs activation and induction of interferon-related genes, suggesting that failure to activate TEs may account for the weak interferon response. Moreover, we identify two variables that explain most of the observed diverseness in immune responses: basal expression levels of TEs in the pre-infected cells and the viral load. Finally, analyzing the SARS-CoV-2 interactome and the epigenetic landscape around the TEs activated following infection, we identify SARS-CoV-2 interacting proteins, which may regulate chromatin structure and TE transcription. This work provides a possible functional explanation for SARS-CoV-2 success in its fight against the host immune system and suggests that TEs could serve as potential drug targets for COVID-19.

Can't smell the virus: SARS-CoV-2, chromatin organization, and anosmia.

Anosmia, or loss of smell, is strongly associated with SARS-CoV-2 infection in humans, but the underlying mechanism remains obscure. In a recent Cell study, Zazhytska et al. (2022) report non-cell-autonomous disruption of long-range genomic interactions of olfactory receptor genes in response to SARS-CoV-2 infection, and these interactions remain disrupted long after virus clearance.

The upstream 5' splice site remains associated to the transcription machinery during intron synthesis.

In the earliest step of spliceosome assembly, the two splice sites flanking an intron are brought into proximity by U1 snRNP and U2AF along with other proteins. The mechanism that facilitates this intron looping is poorly understood. Using a CRISPR interference-based approach to halt RNA polymerase II transcription in the middle of introns in human cells, we discovered that the nascent 5' splice site base pairs with a U1 snRNA that is tethered to RNA polymerase II during intron synthesis. This association functionally corresponds with splicing outcome, involves bona fide 5' splice sites and cryptic intronic sites, and occurs transcriptome-wide. Overall, our findings reveal that the upstream 5' splice sites remain attached to the transcriptional machinery during intron synthesis and are thus brought into proximity of the 3' splice sites; potentially mediating the rapid splicing of long introns.

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

BACKGROUND: Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained. RESULTS: Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder. CONCLUSIONS: Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.

Correction to: Progerin-Induced Transcriptional Changes in Huntington's Disease Human Pluripotent Stem Cell-Derived Neurons.

In the original version of the paper, the name of one of the contributing authors, Dr. Mundackal S. Divya (orcid:0000-0002-2869-7191).

Progerin-Induced Transcriptional Changes in Huntington's Disease Human Pluripotent Stem Cell-Derived Neurons.

Huntington's disease (HD) is a neurodegenerative late-onset genetic disorder caused by CAG expansions in the coding region of the Huntingtin (HTT) gene, resulting in a poly-glutamine (polyQ) expanded HTT protein. Considerable efforts have been devoted for studying HD and other polyQ diseases using animal models and cell culture systems, but no treatment currently exists. Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer an elegant solution for modeling human diseases. However, as embryonic or rejuvenated cells, respectively, these pluripotent stem cells (PSCs) do not recapitulate the late-onset feature of the disease. Here, we applied a robust and rapid differentiation protocol to derive electrophysiologically active striatal GABAergic neurons from human wild-type (WT) and HD ESCs and iPSCs. RNA-seq analyses revealed that HD and WT PSC-derived neurons are highly similar in their gene expression patterns. Interestingly, ectopic expression of Progerin in both WT and HD neurons exacerbated the otherwise non-significant changes in gene expression between these cells, revealing IGF1 and genes involved in neurogenesis and nervous system development as consistently altered in the HD cells. This work provides a useful tool for modeling HD in human PSCs and reveals potential molecular targets altered in HD neurons.

Open chromatin structure in PolyQ disease-related genes: a potential mechanism for CAG repeat expansion in the normal human population.

The human genome contains dozens of genes that encode for proteins containing long poly-glutamine repeats (polyQ, usually encoded by CAG codons) of 10Qs or more. However, only nine of these genes have been reported to expand beyond the healthy variation and cause diseases. To address whether these nine disease-associated genes are unique in any way, we compared genetic and epigenetic features relative to other types of genes, especially repeat containing genes that do not cause diseases. Our analyses show that in pluripotent cells, the nine polyQ disease-related genes are characterized by an open chromatin profile, enriched for active chromatin marks and depleted for suppressive chromatin marks. By contrast, genes that encode for polyQ-containing proteins that are not associated with diseases, and other repeat containing genes, possess a suppressive chromatin environment. We propose that the active epigenetic landscape support decreased genomic stability and higher susceptibility for expansion mutations.

An Endogenously Tagged Fluorescent Fusion Protein Library in Mouse Embryonic Stem Cells.

Embryonic stem cells (ESCs), with their dual capacity to self-renew and differentiate, are commonly used to study differentiation, epigenetic regulation, lineage choices, and more. Using non-directed retroviral integration of a YFP/Cherry exon into mouse ESCs, we generated a library of over 200 endogenously tagged fluorescent fusion proteins and present several proof-of-concept applications of this library. We show the utility of this library to track proteins in living cells; screen for pluripotency-related factors; identify heterogeneously expressing proteins; measure the dynamics of endogenously labeled proteins; track proteins recruited to sites of DNA damage; pull down tagged fluorescent fusion proteins using anti-Cherry antibodies; and test for interaction partners. Thus, this library can be used in a variety of different directions, either exploiting the fluorescent tag for imaging-based techniques or utilizing the fluorescent fusion protein for biochemical pull-down assays, including immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, and more.

Stochasticity, bistability and the wisdom of crowds: a model for associative learning in genetic regulatory networks.

It is generally believed that associative memory in the brain depends on multistable synaptic dynamics, which enable the synapses to maintain their value for extended periods of time. However, multistable dynamics are not restricted to synapses. In particular, the dynamics of some genetic regulatory networks are multistable, raising the possibility that even single cells, in the absence of a nervous system, are capable of learning associations. Here we study a standard genetic regulatory network model with bistable elements and stochastic dynamics. We demonstrate that such a genetic regulatory network model is capable of learning multiple, general, overlapping associations. The capacity of the network, defined as the number of associations that can be simultaneously stored and retrieved, is proportional to the square root of the number of bistable elements in the genetic regulatory network. Moreover, we compute the capacity of a clonal population of cells, such as in a colony of bacteria or a tissue, to store associations. We show that even if the cells do not interact, the capacity of the population to store associations substantially exceeds that of a single cell and is proportional to the number of bistable elements. Thus, we show that even single cells are endowed with the computational power to learn associations, a power that is substantially enhanced when these cells form a population.