Local chromatin context dictates the genetic determinants of the heterochromatin spreading reaction.
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PROVIDER: PRJNA764251 | ENA |
REPOSITORIES: ENA
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Project description:Heterochromatin spreading, the expansion of gene-silencing structures from DNA-encoded nucleation sites, occurs in distinct settings. Spreading re-establishes gene-poor constitutive heterochromatin every cell cycle, but also invades gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context, i.e. euchromatic, heterochromatic, or different nucleator types, influences the determinants of this process remains poorly understood. Previously, we documented distinct behaviors of heterochromatin spreading in different contexts using a single-cell heterochromatin spreading sensor (Greenstein et al. 2018). In this work, building on this sensor system, we now genetically identify the factors that positively or negatively alter the propensity of a nucleation site to spread heterochromatin. We find that different chromatin contexts are dependent on unique sets of genes for the regulation of heterochromatin spreading. Further, we find that spreading in constitutive heterochromatin requires Clr6 histone deacetylase complexes containing the Fkh2 transcription factor, while the Clr3 deacetylase is globally required for silencing. Fkh2 acts by recruiting Clr6 to nucleation-distal chromatin sites. Our results segregate the pathways that control lateral heterochromatin spreading from those that instruct DNA-directed assembly in nucleation.
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Project description:Domains of heterochromatin play important roles in the maintenance and regulation of eukaryotic genomes. However, the repressive nature of heterochromatin combined with its propensity to self-propagate necessitates the existence of robust mechanisms that limit heterochromatin spreading and thereby avoid silencing of expressed genes. A number of specific sequence elements have been found to serve as barriers to heterochromatin spreading; however, the mechanisms by which spreading is curtailed are generally not well understood. Here we uncover a role for PAF complex component Leo1 in regulating heterochromatin cis-spreading. A genetic screen revealed that loss of Leo1 results in spreading of heterochromatin across a centromeric (IRC) boundary element in fission yeast. Similar heterochromatin spreading was seen upon deletion of other components of the PAF complex, but not other factors involved in transcription-coupled chromatin modification, indicating a specific role for the PAF complex in heterochromatin regulation. Loss of Leo1 is associated with reduced levels of H4K16 acetylation at the boundary, while tethering of the H4K16 acetyltransferase Mst1 to boundary chromatin suppresses heterochromatin spreading in leo1? cells, suggesting that Leo1 antagonises heterochromatin spreading by facilitating H4K16 acetylation. Interestingly, Leo1 also regulates heterochromatin spreading independently of boundaries, and loss of Leo1 causes redistribution of heterochromatin, in particular resulting in substantial expansion of telomeric heterochromatin domains. The PAF complex is known to be an important regulator of transcription-related chromatin modifications; our findings reveal a previously undescribed role for this complex in global regulation of heterochromatin spreading in cis. 8 samples: input (whole cell extract) and IP from H3K9me2 ChIP in wild-type and leo1? cells, in duplicate
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Project description:Domains of heterochromatin play important roles in the maintenance and regulation of eukaryotic genomes. However, the repressive nature of heterochromatin combined with its propensity to self-propagate necessitates the existence of robust mechanisms that limit heterochromatin spreading and thereby avoid silencing of expressed genes. A number of specific sequence elements have been found to serve as barriers to heterochromatin spreading; however, the mechanisms by which spreading is curtailed are generally not well understood. Here we uncover a role for PAF complex component Leo1 in regulating heterochromatin cis-spreading. A genetic screen revealed that loss of Leo1 results in spreading of heterochromatin across a centromeric (IRC) boundary element in fission yeast. Similar heterochromatin spreading was seen upon deletion of other components of the PAF complex, but not other factors involved in transcription-coupled chromatin modification, indicating a specific role for the PAF complex in heterochromatin regulation. Loss of Leo1 is associated with reduced levels of H4K16 acetylation at the boundary, while tethering of the H4K16 acetyltransferase Mst1 to boundary chromatin suppresses heterochromatin spreading in leo1Δ cells, suggesting that Leo1 antagonises heterochromatin spreading by facilitating H4K16 acetylation. Interestingly, Leo1 also regulates heterochromatin spreading independently of boundaries, and loss of Leo1 causes redistribution of heterochromatin, in particular resulting in substantial expansion of telomeric heterochromatin domains. The PAF complex is known to be an important regulator of transcription-related chromatin modifications; our findings reveal a previously undescribed role for this complex in global regulation of heterochromatin spreading in cis.
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Project description:Transposable elements have the potential to act as controlling elements to influence the expression of genes. The current paradigm suggests that heterochromatic silencing can spread beyond the borders of the transposable element and influence the chromatin state of neighboring low-copy sequences. This would allow transposable elements to condition obligatory or facilitated epialleles and act as controlling elements. The maize genome contains numerous families of class I transposable elements (retrotransposons) that are present in moderate to high copy numbers and many are found in regions near genes which provides an opportunity to test whether the spreading of heterochromatin from retrotransposons is prevalent. We have investigated the extent of heterochromatin spreading into flanking DNA around each family of retrotransposons through profiling of DNA methylation and di-methylation of lysine 9 of histone 3 (H3K9me2) in low-copy regions of the maize genome. The effects of different retrotransposon families on local chromatin are highly variable. Some LTR families exhibit enrichment of heterochromatic marks within 800-1200 base pairs of the insertion site while other families have very little evidence for spreading of heterochromatic marks. The analysis of chromatin state in genotypes that lack specific insertions suggests that the adjacent heterochromatin results from spreading of silencing rather than insertion-site preferences. Genes that are located near elements that exhibit spreading of heterochromatin tend to be expressed at lower levels than other genes. Our findings suggest that a subset of LTR retrotransposon families may act as controlling elements influencing neighboring sequences while the majority of elements have little effect on flanking sequences Transposable elements comprise a substantial portion of many eukaryotic genomes. These mobile fragments of DNA can result in mutations through insertions into genes but may also affect the regulation of genes they insert near. There is evidence that the majority of transposable elements are epigenetically silenced and in some cases this silencing may affect neighboring sequences. However, evolutionary theory would predict that there would be selective pressures for transposable elements to limit their effects on neighboring genes. The maize genome has a complex organization with many genes flanked by retrotransposons. We profiled the spread of heterochromatin from the retrotransposons into nearby low copy sequences for 150 high copy retrotransposon families. While the manymajority of retrotransposons exhibit little to no spreading of heterochromatin there are a small number ofsome retrotransposon families that influence the chromatin state of surrounding regions. The families may represent bad “neighbors” that spread heterochromatin and influence nearby genes.
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