Detection and quantification of the histone code in the fungal genus Aspergillus

Zhang, Xin; Noberini, Roberta; Vai, Alessandro; Bonaldi, Tiziana; Seidl, Michael; Collemare, Jérôme

doi:10.1016/j.fgb.2023.103800

Cited by 4 publications

(4 citation statements)

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“…In particular, H3K79me is a relevant candidate as this modification was reported to localize at transition regions between heterochromatin and euchromatin, and we recently reported for this modification differences in abundances between different Aspergilli (X. Zhang et al, 2023). While our understanding of how genomic localization and histone PTMs regulate SM production remains partial, our study points at new directions that might provide new keys to unlock the full potential of SM production in Aspergilli.…”

Section: Discussionmentioning

confidence: 63%

“…To perform RNA sequencing, we obtained the fine powder of young mycelium of A. fumigatus (strain: Af293, CBS 126847), A. nidulans (strain: Wtpaba (genotype: pabaA1)), and A. niger (strain: NRRL3, CBS 120.49) as described previously (X. Zhang et al, 2023). Subsequently, we extracted high-quality total RNA from each species in four replicates, following our inhouse RNA extraction protocol.…”

Section: Rna-seq Sample Preparationmentioning

confidence: 99%

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Secondary metabolite biosynthetic gene clusters and their genomic localization in the fungal genusAspergillus

Zhang,

Leahy,

Collemare

et al. 2024

Preprint

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Fungi are well-known producers of bioactive secondary metabolites (SMs), which have been exploited for centuries by humankind for various medical applications like therapeutics and antibiotics. SMs are synthesized by biosynthetic gene clusters (BGCs) – physically co-localized and co-regulated genes. Because BGCs are often regulated by histone post-translational modifications (PTMs), it was suggested that their chromosomal location is important for their expression. Studies in a few fungal species indicated an enrichment of BGCs in sub-telomeric regions, however, there is no evidence that BGCs with distinct genomic localization are regulated by different histone PTMs. Here, we used 174Aspergillusspecies covering 22 sections to determine the correlation between BGC genomic localization, gene expression, and histone PTMs. We found a high abundance and diversity of SM backbone genes across theAspergillusgenus, with notable diversity increases between sections. Being unique or conserved in many species, BGCs showed a strong bias for being localized in low-synteny regions, regardless of their position in chromosomes. Using chromosome-level assemblies, we also confirmed a significantly biased localization in sub-telomeric regions. Notably, SM backbone genes in sub-telomeric regions and about half of those in low-synteny regions exhibit higher gene expression variability, likely due to the similar higher variability in H3K4me3 and H3K36me3 histone PTMs. In contrast, variations in histone H3 acetylation and H3K9me3 are not correlated to genomic localization and expression variation. Overall, our results indicate that BGCs tend to be located in low-synteny regions and that regulation of expression in those regions likely involves different histone PTMs than the most commonly studied modifications.SignificanceFungi are known for producing a myriad of bioactive compounds with medical benefits, yet our understanding of how the production of these compounds is regulated remains limited. Here, we focused on the fungal genusAspergillus, containing many species known to be prolific producers of bioactive compounds, to systematically uncover the diversity and genomic localization of biosynthetic pathways. By expanding our knowledge beyond the few commonly studied fungal species, this research offers novel insights into how the genomic localization of biosynthetic pathways matters for the regulation of their expression. Our results pave the way for the discovery and harnessing of new fungal metabolites for medical and industrial applications.

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Section: Discussionmentioning

confidence: 63%

Section: Rna-seq Sample Preparationmentioning

confidence: 99%

Secondary metabolite biosynthetic gene clusters and their genomic localization in the fungal genusAspergillus

Zhang,

Leahy,

Collemare

et al. 2024

Preprint

Self Cite

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“…The H3K9me3 and H3K14ac play crucial roles in fungal development, virulence, and SMs ( Gu et al, 2017 ; Chen et al, 2022 ; Zhang et al, 2023 ), with the former typically associated with gene repression ( Gessaman and Selker, 2017 ) and the latter with gene activation ( Wang et al, 2017 ). In order to gain a deeper understanding of the impact of Bchda1 and Bcdim5 loss on H3K9me3 and H3K14ac occupancy in strains, ChIP-seq was conducted to map the genomic distribution of these modifications in the Δ Bcdim5 and Δ Bchda1 mutants, with B. cinerea TB-31 serving as a background control ( Supplementary Dataset S2 ).…”

Section: Resultsmentioning

confidence: 99%

Normal distribution of H3K9me3 occupancy co-mediated by histone methyltransferase BcDIM5 and histone deacetylase BcHda1 maintains stable ABA synthesis in Botrytis cinerea TB-31

Wei,

Shu,

Hou

et al. 2024

Front. Microbiol.

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Abscisic acid (ABA) is a conserved and important “sesquiterpene signaling molecule” widely distributed in different organisms with unique biological functions. ABA coordinates reciprocity and competition between microorganisms and their hosts. In addition, ABA also regulates immune and stress responses in plants and animals. Therefore, ABA has a wide range of applications in agriculture, medicine and related fields. The plant pathogenic ascomycete B. cinerea has been extensively studied as a model strain for ABA production. Nevertheless, there is a relative dearth of research regarding the regulatory mechanism governing ABA biosynthesis in B. cinerea. Here, we discovered that H3K9 methyltransferase BcDIM5 is physically associated with the H3K14 deacetylase BcHda1. Deletion of Bcdim5 and Bchda1 in the high ABA-producing B. cinerea TB-31 led to severe impairment of ABA synthesis. The combined analysis of RNA-seq and ChIP-seq has revealed that the absence of BcDIM5 and BcHda1 has resulted in significant global deficiencies in the normal distribution and level of H3K9me3 modification. In addition, we found that the cause of the decreased ABA production in the ΔBcdim5 and ΔBchda1 mutants was due to cluster gene repression caused by the emergence of hyper-H3K9me3 in the ABA gene cluster. We concluded that the ABA gene cluster is co-regulated by BcDIM5 and BcHda1, which are essential for the normal distribution of the B. cinerea TB-31 ABA gene cluster H3K9me3. This work expands our understanding of the complex regulatory network of ABA biosynthesis and provides a theoretical basis for genetic improvement of high-yielding ABA strains.

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“…Histones were enriched from 0.2 to 4 × 10 6 MCF7 or T47D cells as previously described ( 59 ). Approximately 4 μg of histone octamer were mixed with an equal amount of heavy-isotope labeled histones, which were used as an internal standard (super-SILAC mix; ref.…”

Section: Methodsmentioning

confidence: 99%

Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells

Rosano,

Sofyali,

Dhiman

et al. 2024

Cancer Discovery

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Patients with estrogen receptor–positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs. Significance: This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs.

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Detection and quantification of the histone code in the fungal genus Aspergillus

Cited by 4 publications

References 62 publications

Secondary metabolite biosynthetic gene clusters and their genomic localization in the fungal genusAspergillus

Secondary metabolite biosynthetic gene clusters and their genomic localization in the fungal genusAspergillus

Normal distribution of H3K9me3 occupancy co-mediated by histone methyltransferase BcDIM5 and histone deacetylase BcHda1 maintains stable ABA synthesis in Botrytis cinerea TB-31

Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells

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