Retention Of Transcription Factors Research Articles

Loss of H3K9 trimethylation alters chromosome compaction and transcription factor retention during mitosis

Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases and polycomb repressor complexes, binds to chromosomes throughout mitosis and their depletion results in increased chromosome size. In the present study, we show that enzymes that catalyze H3K9 methylation, such as Suv39h1, Suv39h2, G9a and Glp, are also retained on mitotic chromosomes. Surprisingly, however, mutants lacking histone 3 lysine 9 trimethylation (H3K9me3) have unusually small and compact mitotic chromosomes associated with increased histone H3 phospho Ser10 (H3S10ph) and H3K27me3 levels. Chromosome size and centromere compaction in these mutants were rescued by providing exogenous first protein lysine methyltransferase Suv39h1 or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wild-type versus Suv39h1/Suv39h2 double-null mouse embryonic stem cells revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.

Transcription factor retention through multiple polyploidization steps in wheat.

Whole-genome duplication is widespread in plant evolutionary history and is followed by nonrandom gene loss to return to a diploid state. Across multiple angiosperm species, the retained genes tend to be dosage-sensitive regulatory genes such as transcription factors, yet data for younger polyploid species is sparse. Here, we analyzed the retention, expression, and genetic variation in transcription factors in the recent allohexaploid bread wheat (Triticum aestivum L.). By comparing diploid, tetraploid, and hexaploid wheat, we found that, following each of two hybridization and whole-genome duplication events, the proportion of transcription factors in the genome increased. Transcription factors were preferentially retained over other genes as homoeologous groups in tetraploid and hexaploid wheat. Across cultivars, transcription factor homoeologs contained fewer deleterious missense mutations than nontranscription factors, suggesting that transcription factors are maintained as three functional homoeologs in hexaploid wheat populations. Transcription factor homoeologs were more strongly coexpressed than nontranscription factors, indicating conservation of function between homoeologs. We found that the B3, MADS-M-type, and NAC transcription factor families were less likely to have three homoeologs present than other families, which was associated with low expression levels and high levels of tandem duplication. Together, our results show that transcription factors are preferentially retained in polyploid wheat genomes although there is variation between families. Knocking out one transcription factor homoeolog to alter gene dosage, using TILLING or CRISPR, could generate new phenotypes for wheat breeding.

Interferon stimulation creates chromatin marks and establishes transcriptional memory

Epigenetic memory for signal-dependent transcription has remained elusive. So far, the concept of epigenetic memory has been largely limited to cell-autonomous, preprogrammed processes such as development and metabolism. Here we show that IFNβ stimulation creates transcriptional memory in fibroblasts, conferring faster and greater transcription upon restimulation. The memory was inherited through multiple cell divisions and led to improved antiviral protection. Of ∼2,000 IFNβ-stimulated genes (ISGs), about half exhibited memory, which we define as memory ISGs. The rest, designated nonmemory ISGs, did not show memory. Surprisingly, mechanistic analysis showed that IFN memory was not due to enhanced IFN signaling or retention of transcription factors on the ISGs. We demonstrated that this memory was attributed to accelerated recruitment of RNA polymerase II and transcription/chromatin factors, which coincided with acquisition of the histone H3.3 and H3K36me3 chromatin marks on memory ISGs. Similar memory was observed in bone marrow macrophages after IFNγ stimulation, suggesting that IFN stimulation modifies the shape of the innate immune response. Together, external signals can establish epigenetic memory in mammalian cells that imparts lasting adaptive performance upon various somatic cells.

Transcription factor retention on mitotic chromosomes: regulatory mechanisms and impact on cell fate decisions.

During mitosis, gene transcription stops, and the bulk of DNA-binding proteins are excluded from condensed chromosomes. While most gene-specific transcription factors are largely evicted from mitotic chromosomes, a subset remains bound to specific and non-specific DNA sites. Here, we review the current knowledge on the mechanisms leading to the retention of a subset of transcription factors on mitotic chromosomes and discuss the implications in gene expression regulation and their potential as an epigenetic mechanism controlling stem cell self-renewal and differentiation.

Both mechanism and age of duplications contribute to biased gene retention patterns in plants

BackgroundAll extant seed plants are successful paleopolyploids, whose genomes carry duplicate genes that have survived repeated episodes of diploidization. However, the survival of gene duplicates is biased with respect to gene function and mechanism of duplication. Transcription factors, in particular, are reported to be preferentially retained following whole-genome duplications (WGDs), but disproportionately lost when duplicated by tandem events. An explanation for this pattern is provided by the Gene Balance Hypothesis (GBH), which posits that duplicates of highly connected genes are retained following WGDs to maintain optimal stoichiometry among gene products; but such connected gene duplicates are disfavored following tandem duplications.ResultsWe used genomic data from 25 taxonomically diverse plant species to investigate the roles of duplication mechanism, gene function, and age of duplication in the retention of duplicate genes. Enrichment analyses were conducted to identify Gene Ontology (GO) functional categories that were overrepresented in either WGD or tandem duplications, or across ranges of divergence times. Tandem paralogs were much younger, on average, than WGD paralogs and the most frequently overrepresented GO categories were not shared between tandem and WGD paralogs. Transcription factors were overrepresented among ancient paralogs regardless of mechanism of origin or presence of a WGD. Also, in many cases, there was no bias toward transcription factor retention following recent WGDs.ConclusionsBoth the fixation and the retention of duplicated genes in plant genomes are context-dependent events. The strong bias toward ancient transcription factor duplicates can be reconciled with the GBH if selection for optimal stoichiometry among gene products is strongest following the earliest polyploidization events and becomes increasingly relaxed as gene families expand.

Architectural Genetic and Epigenetic Control of Regulatory Networks: Compartmentalizing Machinery for Transcription and chromatin remodeling in nuclear Microenvironments

The regulatory machinery that governs genetic and epigenetic control of gene expression for biological processes and cancer is organized in nuclear microenvironments. Strategic placement of transcription factors at target gene promoters in punctate microenvironments of interphase nuclei supports scaffolding of co- regulatory proteins and the convergence as well as integration of regulatory networks. The organization and localization of regulatory complexes within the nucleus can provide signatures that are linked to regulatory activity. Retention of transcription factors at gene loci in mitotic chromosomes contributes to epigenetic control of cell fate and lineage commitment, as well as to persistence of transformed and tumor phenotypes. Mechanistic understanding of the architectural assembly of regulatory machinery can serve as a basis for treating cancer with high specificity and minimal off-target effects.