It is commonly accepted that genetic sequences coded within DNA are passed down through generations and can influence characteristics such as appearance, behavior and health. However, emerging evidence suggests that some traits can also be inherited ‘epigenetically’ from information that is independent of the DNA sequence.
One of the ways characteristics may be epigenetically passed down is through the temporary modification of histone proteins which help to package DNA into the cell. Histones are adorned with chemical marks that can regulate how and when a gene is expressed by changing how tightly the DNA is wrapped. These marks are typically removed before genetic information is passed on to the next generation, but some sites escape erasure (Heard and Martienssen, 2014; Kelly, 2014; Miska and Ferguson-Smith, 2016).
It has previously been reported that genetic mutations in an enzyme complex called COMPASS increase the lifespan of tiny worms called Caenorhabditis elegans (Greer et al., 2010). This complex acts on histones and creates a chemical mark called H3K4me, which is typically associated with less compact DNA and higher gene expression. When these mutants mate with wild-type worms they generate descendants that no longer have COMPASS mutations. Although these wild-type offspring recover normal levels of H3K4me, they still inherit the long-lived phenotype which they sustain for several generations (Greer et al., 2011). This observation suggests that an epigenetic mechanism that is independent from the gene mutation causes this inherited longevity. Now, in eLife, David Katz and co-workers at the Emory University School of Medicine in Atlanta – including Teresa Lee as first author – report a possible mechanism to explain how this longer lifespan is epigenetically inherited across multiple generations (Lee et al., 2019).
Previous work showed that one of the COMPASS complex mutants, known as wdr-5, has increased levels of another histone mark called H3K9me2 (Kerr et al., 2014). This epigenetic mark generally promotes DNA compaction and appears to antagonize the action of H3K4me. This led Lee et al. to question whether the elevated levels of H3K9me2 may be important for the inheritance of this extended lifespan in wdr-5 worms.
To test their hypothesis, the team carefully monitored the levels and patterns of H3K9me2 in the mutants. Surprisingly, they found that homozygous wdr-5 mutants, which had descended from ancestors carrying one copy of the mutated wdr-5 gene and one wild-type copy for multiple generations, did not live for longer than their non-mutant counterparts. This indicates that the mutation carried by wdr-5 worms did not immediately cause a lifespan change. However, future generations of worms that maintained the homozygous wdr-5 mutation had an increasingly longer lifespan, suggesting that the accumulation of an epigenetic signal across generations promotes longer living. These late generation wdr-5 mutants had higher levels of H3K9me2, and they were able to pass on this extended longevity to their progeny following mating with wild-type worms as previously reported (Greer et al., 2011).
Next, Lee et al. manipulated the levels of H3K9me2 to see how this affected the phenotype of the late generation, long-lived wdr-5 worms. First, they blocked the gain in H3K9me2 levels in the mutants by introducing a defective version of an enzyme called MET-2 which normally promotes the addition of H3K9me2 (Figure 1). As a result, neither the wdr-5 mutants nor their descendants experienced a longer lifespan. Lee et al. reasoned that if higher H3K9me2 levels are responsible for longevity, then increasing the amount of H3K9me2 by a different mutation should result in the same phenotype as the wdr-5 worms. They found that worms with defects in the enzyme JHDM-1, which is predicted to remove H3K9me2, not only lived longer but also passed on this trait to their wild-type progeny for several generations. Together, these data strongly suggest that increased H3K9me2 levels contribute to extended longevity and its inheritance.
To build on these findings, Lee et al. explored where the H3K9me2 marks were deposited in the genomes of the worms. As expected, long-lived wdr-5 and jhdm-1 mutants have more H3K9me2 marks spread across their genomes. Critically, Lee et al. found that specific genes in the wild-type offspring of jhdm-1 mutants had higher levels of H3K9me2. These results are intriguing and suggest that increasing H3K9me2 levels in certain genes may be the key to passing on this long living phenotype to future generations. Exciting future investigations will be to identify all the gene regions associated with the inherited increase in H3K9me2, and to understand how changes to DNA packaging and gene expression in those regions influence longevity.
A handful of previous studies in C. elegans have demonstrated that specific histone modifications can be inherited across generations (Katz et al., 2009; Kerr et al., 2014; Kaneshiro et al., 2019). However, the paper by Lee et al. is the first to tie together the inheritance of a histone mark to longer lifespan. H3K9me2 is an evolutionarily conserved histone mark which is known to preserve spatial organization during cell division in organisms ranging from humans to worms (Poleshko et al., 2019). Going forward, it will be interesting to study whether H3K9me2 also participates in how traits are inherited across multiple generations in mammals.
To mount a protective response to infection while preventing hyperinflammation, gene expression in innate immune cells must be tightly regulated. Despite the importance of pre-mRNA splicing in shaping the proteome, its role in balancing immune outcomes remains understudied. Transcriptomic analysis of murine macrophage cell lines identified Serine/Arginine Rich Splicing factor 6 (SRSF6) as a gatekeeper of mitochondrial homeostasis. SRSF6-dependent orchestration of mitochondrial health is directed in large part by alternative splicing of the pro-apoptosis pore-forming protein BAX. Loss of SRSF6 promotes accumulation of BAX-κ, a variant that sensitizes macrophages to undergo cell death and triggers upregulation of interferon stimulated genes through cGAS sensing of cytosolic mitochondrial DNA. Upon pathogen sensing, macrophages regulate SRSF6 expression to control the liberation of immunogenic mtDNA and adjust the threshold for entry into programmed cell death. This work defines BAX alternative splicing by SRSF6 as a critical node not only in mitochondrial homeostasis but also in the macrophage’s response to pathogens.
Asynchronous replication of chromosome domains during S phase is essential for eukaryotic genome function, but the mechanisms establishing which domains replicate early versus late in different cell types remain incompletely understood. Intercalary heterochromatin domains replicate very late in both diploid chromosomes of dividing cells and in endoreplicating polytene chromosomes where they are also underrelicated. Drosophila SNF2-related factor SUUR imparts locus-specific underreplication of polytene chromosomes. SUUR negatively regulates DNA replication fork progression; however, its mechanism of action remains obscure. Here we developed a novel method termed MS-Enabled Rapid protein Complex Identification (MERCI) to isolate a stable stoichiometric native complex SUMM4 that comprises SUUR and a chromatin boundary protein Mod(Mdg4)-67.2. Mod(Mdg4) stimulates SUUR ATPase activity and is required for a normal spatiotemporal distribution of SUUR in vivo. SUUR and Mod(Mdg4)-67.2 together mediate the activities of gypsy insulator that prevent certain enhancer-promoter interactions and establish euchromatin-heterochromatin barriers in the genome. Furthermore, SuUR or mod(mdg4) mutations reverse underreplication of intercalary heterochromatin. Thus, SUMM4 can impart late replication of intercalary heterochromatin by attenuating the progression of replication forks through euchromatin/heterochromatin boundaries. Our findings implicate a SNF2 family ATP-dependent motor protein SUUR in the insulator function, reveal that DNA replication can be delayed by a chromatin barrier and uncover a critical role for architectural proteins in replication control. They suggest a mechanism for the establishment of late replication that does not depend on an asynchronous firing of late replication origins.