Histone crotonylation specifically marks the haploid male germ cell gene expression program

Montellier, Emilie; Rousseaux, Sophie; Zhao, Yingming; Khochbin, Saadi

doi:10.1002/bies.201100141

Cited by 100 publications

(88 citation statements)

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“…Several lab mouse mutants with normal MSCI exhibit global derepression of the sex chromosomes in postmeiotic spermatids (reviewed in Montellier et al 2011). In particular, the multicopy Y-linked gene, Sly, is essential for normal sperm differentiation and is a key regulator of PSCR (Reynard et al 2009;).…”

Section: Postmeiotic Overexpressionmentioning

confidence: 99%

“…Thus, defective PSCR in the sterile F 1 may be a secondary consequence of disrupted MSCI. It is possible, however, that X overexpression in meiotic cells vs. postmeiotic cells is caused by distinct genetic incompatibilities between domesticus LEWES -derived loci and loci on the musculus PWK X.Several lab mouse mutants with normal MSCI exhibit global derepression of the sex chromosomes in postmeiotic spermatids (reviewed in Montellier et al 2011). In particular, the multicopy Y-linked gene, Sly, is essential for normal sperm differentiation and is a key regulator of PSCR (Reynard et al 2009;).…”

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Meiotic Sex Chromosome Inactivation Is Disrupted in Sterile Hybrid Male House Mice

2013

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In male mammals, the X and Y chromosomes are transcriptionally silenced in primary spermatocytes by meiotic sex chromosome inactivation (MSCI) and remain repressed for the duration of spermatogenesis. Here, we test the longstanding hypothesis that disrupted MSCI might contribute to the preferential sterility of heterogametic hybrid males. We studied a cross between wildderived inbred strains of Mus musculus musculus and M. m. domesticus in which sterility is asymmetric: F 1 males with a M. m. musculus mother are sterile or nearly so while F 1 males with a M. m. domesticus mother are normal. In previous work, we discovered widespread overexpression of X-linked genes in the testes of sterile but not fertile F 1 males. Here, we ask whether this overexpression is specifically a result of disrupted MSCI. To do this, we isolated cells from different stages of spermatogenesis and measured the expression of several genes using quantitative PCR. We found that X overexpression in sterile F 1 primary spermatocytes is coincident with the onset of MSCI and persists in postmeiotic spermatids. Using a series of recombinant X genotypes, we then asked whether X overexpression in hybrids is controlled by cis-acting loci across the X chromosome. We found that it is not. Instead, one large interval in the proximal portion of the M. m. musculus X chromosome is associated with both overexpression and the severity of sterility phenotypes in hybrids. These results demonstrate a strong association between X-linked hybrid male sterility and disruption of MSCI and suggest that transacting loci on the X are important for the transcriptional regulation of the X chromosome during spermatogenesis. FORTY years ago, Lifschytz and Lindsley (1972) proposed the provocative hypothesis that the X chromosome is inactivated during male meiosis and that disruption of this process could lead to sterility. The idea that failure of meiotic sex chromosome inactivation (MSCI) might cause sterility is significant in speciation genetics since it provides a possible explanation for the widespread observation that in crosses between species, sterility typically appears first in the heterogametic sex (Haldane 1922;Forejt 1996;Presgraves 2008).Whether MSCI takes place in Drosophila has been debated for several decades (Kremer et al. 1986;McKee and Handel 1993;Hense et al. 2007;Vibranovski et al. 2009). Current evidence suggests that expression on the X chromosome is suppressed relative to the autosomes during spermatogenesis but that this suppression precedes meiosis and thus does not reflect MSCI (Meiklejohn et al. 2011; but see Vibranovski et al. 2012). Likewise, the sex chromosomes are not differentially silenced in chicken oocytes (Guioli et al. 2012). Therefore, failed MSCI cannot explain hybrid sterility in all female-heterogametic taxa. In therian mammals, however, MSCI is well established (Solari 1974;McKee and Handel 1993;Namekawa et al. 2007). Although no MSCI-essential loci have been found on the sex chromosomes, many of the autosomal genes t...

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Section: Postmeiotic Overexpressionmentioning

confidence: 99%

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confidence: 99%

Meiotic Sex Chromosome Inactivation Is Disrupted in Sterile Hybrid Male House Mice

2013

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“…Among the hundreds of different PTMs, acylations at lysine residues, such as acetylation (3)(4)(5)(6), malonylation (7,8), crotonylation (9,10), propionylation (11)(12)(13), butyrylation (11,13), and succinylation (7, 14 -16) are crucial for functional regulations of many prokaryotic and eukaryotic proteins. Because these lysine PTMs depend on the acyl-CoA metabolic intermediates, such as acetyl-CoA (Ac-CoA), succinyl-CoA, and malonylCoA, lysine acylation could provide a mechanism to respond to changes in the energy status of the cell and regulate energy metabolism and the key metabolic pathways in diverse organisms (17,18).…”

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confidence: 99%

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

Yang

Wang

Chen

et al. 2015

Molecular & Cellular Proteomics

120

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Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, remains one of the most prevalent human pathogens and a major cause of mortality worldwide. Metabolic network is a central mediator and defining feature of the pathogenicity of Mtb. Increasing evidence suggests that lysine succinylation dynamically regulates enzymes in carbon metabolism in both bacteria and human cells; however, its extent and function in Mtb remain unexplored. Here, we performed a global succinylome analysis of the virulent Mtb strain H37Rv by using high accuracy nano-LC-MS/MS in combination with the enrichment of succinylated peptides from digested cell lysates and subsequent peptide identification. In total, 1545 lysine succinylation sites on 626 proteins were identified in this pathogen. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the central metabolism pathway. Site-specific mutations showed that succinylation is a negative regulatory modification on the enzymatic activity of acetylCoA synthetase. Molecular dynamics simulations demonstrated that succinylation affects the conformational stability of acetyl-CoA synthetase, which is critical for its enzymatic activity. Further functional studies showed that CobB, a sirtuin-like deacetylase in Mtb, functions as a desuccinylase of acetyl-CoA synthetase in in vitro assays. Together, our findings reveal widespread roles for lysine succinylation in regulating metabolism and diverse processes in Mtb. Our data provide a rich resource for functional analyses of lysine succinylation and facilitate the dissection of metabolic networks in this life-threatening pathogen.

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“…11 Recently it was discovered that HDAC3 exhibits decrotonylase activity in vitro 13 and it was found that lysine crotonylation activates genes even in a globally repressive environment. 7,14 In order to enable investigation of the new lysine derivatives in histones it is essential to generate histones that contain these amino acids site specifically. 15 In this direction semi-synthetic chemical ligation based methods 16,17 were utilized and chemical methods were employed to generate acetyllysine (Kac) and methylated-lysines or derivatives thereof.…”

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Synthesis of ε-N-propionyl-, ε-N-butyryl-, and ε-N-crotonyl-lysine containing histone H3 using the pyrrolysine system

2013

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Recently new lysine modifications were detected in histones and other proteins. Using the pyrrolysine amber suppression system we genetically inserted three of the new amino acids e-N-propionyl-, e-N-butyryl-, and e-N-crotonyl-lysine site specifically into histone H3. The lysine at position 9 (H3 K9), which is known to be highly modified in chromatin, was replaced by these unnatural amino acids.The histone code is based on the post-translational modification of critical amino acid residues in different histones. Among these, lysine acetylations and methylations are the most abundant and affect the transcriptional status of the genes associated with the corresponding histones. [1][2][3] The role of these modifications is sequence dependent. Typically acetylation is associated with transcriptionally active genes, while methylation induces transcriptional silencing. 4,5 Recently Zhao and co-workers discovered a number of new modified amino acids in histones. [6][7][8] Some of these were also detected in proteins other than histones, raising the possibility that they are of more widespread importance. [9][10][11] The new post-translational modifications (PTMs) are acylated derivatives of lysine at the e-amino position. The acylation partners are propionic acid, butyric acid, malonic acid, succinic acid, crotonic acid or fatty acids. A common characteristic of these compounds is that they are key metabolic intermediates that typically exist as CoA activated thioester species in the cell. 12 It is currently not clear how these newly discovered PTMs are biosynthetically established within the histones and we do not fully understand if and how they influence genetic processes.So far no specific deacylases for e-N-propionyl-or e-Nbutyryl-lysine have been identified. However Sirt5, a member of NAD-dependent sirtuins is able to specifically deacylate e-Nmalonyl-and e-N-succinyllysine. 11 Recently it was discovered that HDAC3 exhibits decrotonylase activity in vitro 13 and it was found that lysine crotonylation activates genes even in a globally repressive environment. 7,14 In order to enable investigation of the new lysine derivatives in histones it is essential to generate histones that contain these amino acids site specifically. 15 In this direction semi-synthetic chemical ligation based methods 16,17 were utilized and chemical methods were employed to generate acetyllysine (Kac) and methylated-lysines or derivatives thereof. [18][19][20][21] Chin and co-workers reported the introduction of Kac into H3 K56 22 using the pyrrolysine system. This system was also employed for the synthesis of monomethyl-and dimethyl-lysine containing histones. 23,24 Schultz et al. recently described the synthesis of histone H2B containing e-N-crotonyllysine at position K11 using an evolved pyrrolysyl-tRNA synthetase from Methanosarcina barkeri. 25 Here we show that the pyrrolysine system can be used to insert e-N-propionyl-(Kpr, 1), e-N-butyryl-(Kbu, 2), and e-Ncrotonyl-lysine (Kcr, 3) into histones at critical positions such as H3 K9 using...

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Histone crotonylation specifically marks the haploid male germ cell gene expression program

Cited by 100 publications

References 46 publications

Meiotic Sex Chromosome Inactivation Is Disrupted in Sterile Hybrid Male House Mice

Meiotic Sex Chromosome Inactivation Is Disrupted in Sterile Hybrid Male House Mice

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

Synthesis of ε-N-propionyl-, ε-N-butyryl-, and ε-N-crotonyl-lysine containing histone H3 using the pyrrolysine system

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