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Synthetic facultative heterochromatin as a driver of evolvability

ABSTRACT: Background: Epigenetic regulation has long been hypothesized to enhance evolvability by generating heritable, selectable phenotypic variation. However, experimental evidence linking chromatin-based mechanisms to adaptive evolution remains lacking, because endogenous epigenetic systems are deeply integrated into essential developmental and regulatory networks, making it nearly impossible to perturb or remove them. Here, we report construction of a minimal Polycomb group silencing system in Saccharomyces cerevisiae (yeast), an organism that naturally lacks H3K27me3-based heterochromatin. This synthetic epigenetic circuit enables programmable, locus-specific facultative heterochromatin formation and exhibits mitotically heritable gene silencing. Using this system, we show epigenetic repression generates transcriptional heterogeneity under stress, biasing phenotypic variation to accelerate the emergence and fixation of adaptive mutations. These findings establish a mechanistic link between facultative heterochromatin and enhanced evolvability, and provide a tractable platform for engineering and interrogating the evolutionary consequences of chromatin state dynamics.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE307338 | GEO | 2026/09/06

REPOSITORIES: GEO

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Project description:The prevailing theory for the molecular basis of evolution involves genetic mutations that ultimately generate the heritable phenotypic variation on which natural selection acts. However, epigenetic transgenerational inheritance of phenotypic variation may also play an important role in evolutionary change. A growing number of studies have demonstrated the presence of epigenetic inheritance in a variety of different organisms that can persist for hundreds of generations. The possibility that epigenetic changes could accumulate over macroevolutionary time has been considered, but not yet seldom been tested empirically. The current study was designed to compare epigenetic changes among several closely related species of Darwin’s finches, a well-known example of adaptive radiation. Erythrocyte DNA was obtained from five species of sympatric Darwin's finches that vary in phylogenetic relatedness. Genome wide alterations in genetic mutations using copy number variation (CNV) were compared to epigenetic alterations associated with differential DNA methylation regions (epimutations). Epimutations were more common than genetic CNV mutations among the five species; furthermore, the number of epimutations increased monotonically with phylogenetic distance. Interestingly, the number of genetic CNV mutations did not consistently increase with phylogenetic distance. The number, chromosomal locations, regional clustering, and lack of overlap of epimutations and genetic mutations suggests that epigenetic changes are distinct and that they correlate with the evolutionary history of Darwin’s finches. The potential functional significance of the epimutations was explored by comparing their locations on the genome to the location of evolutionarily important genes and cellular pathways in birds. Specific epimutations were associated with genes related to the bone morphogenic protein (BMP), toll receptor, and melanogenesis signaling pathways. Species- specific epimutations were significantly over-represented in these pathways. Since environmental factors are known to rapidly alter heritable changes in the epigenome, it is possible that epigenetic changes have played a contributing role in the molecular basis of the evolution of Darwin's finches.

Project description:Background Genetic variation drives phenotypic diversity and disease susceptibility. Trans-acting genetic variation coordinates genome-wide chromatin changes, yet the molecular mechanisms underlying this regulation remain largely unknown. Here, we use the power of mouse genetics to investigate how genetic variation at trans-acting loci regulates 3D chromatin interactions. Results Genetically variable 3D interactions were identified using HiChIP to map H3K27ac-associated regulatory elements in C57BL/6J (B6) and DBA/2J (D2) embryonic stem cells (ESCs). We identified 4,962 strain-differential interactions (~5% of total interactions), 71% of which overlapped chromatin accessibility quantitative trait loci (caQTL), establishing that chromatin interaction variation is predominantly heritable. These differential interactions showed coordinated changes in chromatin state and gene expression, with stronger interactions associated with increased accessibility and transcription. Notably, loci regulated in trans exhibited a unique chromatin signature where weaker interactions were enriched for H3K9me3-marked heterochromatin. This pattern was 20-fold more enriched at trans-regulated targets compared to cis, implicating heterochromatin in trans-regulation of 3D genome structure. Analysis of F1 hybrids revealed dominant repressive effects, consistent with heterochromatin-mediated trans-regulation. To causally test this mechanism, we generated reciprocal congenic mouse strains carrying a Chr13 trans-QTL region on otherwise inbred genetic backgrounds. Integrated multiomic profiling of congenic ESC lines demonstrated that this single locus coordinates changes in H3K9me3, H3K27ac, chromatin accessibility, and 3D contact frequency at hundreds of distal genomic regions. Remarkably, 73-83% of differential interactions at Chr13 trans-QTL targets changed in the predicted direction, demonstrating that heterochromatin-mediated trans-regulation coordinately regulates hundreds of regulatory loci. Conclusions This work establishes heterochromatin formation as a mechanism by which genetic variation at trans-acting loci coordinates changes across chromatin accessibility, histone modifications, and 3D genome organization, providing a framework for understanding how early developmental chromatin states could generate phenotypic variation while preserving essential developmental programs.

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Synthetic facultative heterochromatin as a driver of evolvability

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