Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner

Linker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we identify a function of histone H1 in chromatin structure and transcription using a range of genomic approaches. In the absence of histone H1, there is an increase in the transcription of non-coding RNAs, together with reduced levels of m6A modification leading to their accumulation on chromatin and causing replication-transcription conflicts. This strongly suggests that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism, and DNA replication to maintain genome performance.Work at the M.G. lab was supported by the Spanish Ministry of Sciences and Innovation (BFU2016-78849-P and PID2019-105949GB-I00, co-financed by the European Union FEDER funds), a CSIC grant (2019AEP004), and a Salvador de Madariaga mobility grant (PRX19/00293). J.M.F.-J., C.S.-M., and J.I.-A. were supported by the Spanish Ministry of Sciences and Innovation fellowships (BES-2014-070050, BES-2017-079897, and PRE2020-095071, respectively); S.M.-V. was supported by a predoctoral fellowship from the Spanish Ministry of Education and Universities (FPU18/04794); and M.S.-P. was supported by an AGAUR-FI predoctoral fellowship co-financed by Generalitat de Catalunya and the European Social Fund. A.J. was supported by the Spanish Ministry of Sciences and Innovation (BFU2017-82805-C2-1-P and PID2020-112783GB-C21) and J.F.C. by core funding to the MRC Human Genetics Unit from the Medical Research Council (UK)

Asociación entre Artritis Reumatoidea y otras enfermedades autoinmunes

Objetivos: determinar la frecuencia de enfermedades autoinmunes (EAI) en pacientes con Artritis Reumatoidea (AR) y comparar la frecuencia de EAI entre pacientes con AR y sin AR ni otra EAI reumatológica. Material y Métodos: estudio multicéntrico, observacional, analítico, retrospectivo. Se incluyeron pacientes consecutivos con AR (ACR/EULAR 2010) y como grupo control pacientes con diagnóstico inicial de Osteoartritis primaria (OA).

Systematic characterization of the genome-wide and nuclear distribution of six linker histone H1 variants in human cancer cells

[eng] The histone H1 family comprises up to seven members in human somatic cells. However, H1 studies have been limited by the lack of specific ChIP-grade antibodies. Here, we have mapped six endogenous H1 variants in T47D breast cancer cells, which represent the whole somatic H1 complement in this cell line. ChIP-Seq experiments indicate that H1 variants are categorized into two large groups depending on the local GC content: H1.0, H1.2, H1.3 and H1.5 are enriched at low-GC regions while H1.4 and H1X are more abundant at high-GC genomic regions. Data also uncovers common features for H1 variants, highlighting the existing balance between redundancy and specificity. Examination of H1 variants abundance within repetitive elements classes denoted that H1.0, H1.2, H1.3 and H1.5 are enriched within Satellite, LINE, LTR or DNA classes while H1.4 and H1X are enriched within SINE or ‘Other’ classes. This last category comprises SVA retrotransposons, which emerged along hominoid evolution. Interestingly, we have determined that H1X abundance gradually increases from older SVA_A to humanrestricted SVA_F families. This unprecedented association of H1 variants abundance and transposable elements (TEs) evolutionary age is also observed across different TE classes. Both H1X and H1.4 are enriched within the most recently evolved TEs along primate evolution, including not only SVAs but also younger Alu, LINE-L1 or LTR repeats. Conversely, H1.2, H1.3, H1.5, H1.0 are enriched in older TEs. Confocal and super-resolution microscopy experiments further confirm the differential distribution of H1 variants and their distinct contribution to chromatin structure. H1.2, H1.3 and H1.5 are enriched towards the nuclear periphery or lamina-associated domains. H1.4 and H1X show a punctuated pattern throughout the nucleus, with H1X being particularly enriched at nucleoli. H1.0 forms enrichment territories that tend to be peripheral. Moreover, depletion of H1.2, either alone or in combination with H1.4, leads to a general chromatin decompaction that is not observed upon single H1.4 or H1X depletion. Extensive analysis of multiple cell lines revealed the existence of certain universal distribution features despite variations in the H1 somatic repertoire. Specifically, H1.2, H1.3 and H1.5 consistently show enrichments towards the nuclear periphery in all cell lines examined, suggesting their universal role as components of lamina-associated domains. H1X, whose nucleolar presence is evident in all cell lines, is enriched at high- GC regions and younger SVA and Alu elements, as observed in T47D cells. In conclusion, we provide the first systematic comparison of six endogenous H1 variants within a mammalian cell type, while also addressing their differential distribution among multiple cell lines. Altogether, our results support H1 variants heterogeneity and highlight their significance as key organizers and regulators of chromatin

Genomic distribution and functional specificity of human histone H1 variants

Peer reviewe

Differential genomic distribution of human histone H1 variants

Trabajo presentado en Spetses Summer School 2022: Cancer Epigenetics - Principles, applications and single-cell resolution, celebrado en Spetses (Grecia) del 28 de agosto al 03 de septiembre de 2022

TADs enriched in histone H1.2 strongly overlap with the B compartment, inaccessible chromatin, and AT-rich Giemsa bands

Giemsa staining of metaphase chromosomes results in a characteristic banding useful for identification of chromosomes and its alterations. We have investigated in silico whether Giemsa bands (G bands) correlate with epigenetic and topological features of the interphase genome. Staining of G-positive bands decreases with GC content; nonetheless, G-negative bands are GC heterogeneous. High GC bands are enriched in active histone marks, RNA polymerase II, and SINEs and associate with gene richness, gene expression, and early replication. Low GC bands are enriched in repressive marks, lamina-associated domains, and LINEs. Histone H1 variants distribute heterogeneously among G bands: H1X is enriched at high GC bands and H1.2 is abundant at low GC, compacted bands. According to epigenetic features and H1 content, G bands can be organized in clusters useful to compartmentalize the genome. Indeed, we have obtained Hi-C chromosome interaction maps and compared topologically associating domains (TADs) and A/B compartments to G banding. TADs with high H1.2/H1X ratio strongly overlap with B compartment, late replicating, and inaccessible chromatin and low GC bands. We propose that GC content is a strong driver of chromatin compaction and 3D genome organization, that Giemsa staining recapitulates this organization denoted by high-throughput techniques, and that H1 variants distribute at distinct chromatin domains.This work was supported by the Spanish Ministry of Science and Innovation [BFU2017-82805-C2-1-P to AJ, BFU2017-85926-P to MAM-R (AEI/FEDER, UE)]. This research was partially funded by the European Union's Seventh Framework Programme ERC grant agreement 609989 to MAM-R, European Union's Horizon 2020 research and innovation program grant agreement 676556 to MAM-R. We also acknowledge the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-597 to AJ and 2017-SGR-468 to MAM-R. CRG acknowledges support from ‘Centro de Excelencia Severo Ochoa 2013–2017’, SEV-2012-0208, and the CERCA Programme/Generalitat de Catalunya. We acknowledge Generalitat de Catalunya for an AGAUR-FI predoctoral fellowship [to MS-P and to FM]

5-Methylcytosine and 5-Hydroxymethylcytosine in Scrapie-Infected Sheep and Mouse Brain Tissues

Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies or prion diseases, which are caused by an infectious isoform of the innocuous cellular prion protein (PrPC) known as PrPSc. DNA methylation, one of the most studied epigenetic mechanisms, is essential for the proper functioning of the central nervous system. Recent findings point to possible involvement of DNA methylation in the pathogenesis of prion diseases, but there is still a lack of knowledge about the behavior of this epigenetic mechanism in such neurodegenerative disorders. Here, we evaluated by immunohistochemistry the 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in sheep and mouse brain tissues infected with scrapie. Expression analysis of different gene coding for epigenetic regulatory enzymes (DNMT1, DNMT3A, DNMT3B, HDAC1, HDAC2, TET1, and TET2) was also carried out. A decrease in 5mC levels was observed in scrapie-affected sheep and mice compared to healthy animals, whereas 5hmC displayed opposite patterns between the two models, demonstrating a decrease in 5hmC in scrapie-infected sheep and an increase in preclinical mice. 5mC correlated with prion-related lesions in mice and sheep, but 5hmC was associated with prion lesions only in sheep. Differences in the expression changes of epigenetic regulatory genes were found between both disease models, being differentially expressed Dnmt3b, Hdac1, and Tet1 in mice and HDAC2 in sheep. Our results support the evidence that DNA methylation in both forms, 5mC and 5hmC, and its associated epigenetic enzymes, take part in the neurodegenerative course of prion diseases

Brazilian Flora 2020: Leveraging the power of a collaborative scientific network

International audienceThe shortage of reliable primary taxonomic data limits the description of biological taxa and the understanding of biodiversity patterns and processes, complicating biogeographical, ecological, and evolutionary studies. This deficit creates a significant taxonomic impediment to biodiversity research and conservation planning. The taxonomic impediment and the biodiversity crisis are widely recognized, highlighting the urgent need for reliable taxonomic data. Over the past decade, numerous countries worldwide have devoted considerable effort to Target 1 of the Global Strategy for Plant Conservation (GSPC), which called for the preparation of a working list of all known plant species by 2010 and an online world Flora by 2020. Brazil is a megadiverse country, home to more of the world's known plant species than any other country. Despite that, Flora Brasiliensis, concluded in 1906, was the last comprehensive treatment of the Brazilian flora. The lack of accurate estimates of the number of species of algae, fungi, and plants occurring in Brazil contributes to the prevailing taxonomic impediment and delays progress towards the GSPC targets. Over the past 12 years, a legion of taxonomists motivated to meet Target 1 of the GSPC, worked together to gather and integrate knowledge on the algal, plant, and fungal diversity of Brazil. Overall, a team of about 980 taxonomists joined efforts in a highly collaborative project that used cybertaxonomy to prepare an updated Flora of Brazil, showing the power of scientific collaboration to reach ambitious goals. This paper presents an overview of the Brazilian Flora 2020 and provides taxonomic and spatial updates on the algae, fungi, and plants found in one of the world's most biodiverse countries. We further identify collection gaps and summarize future goals that extend beyond 2020. Our results show that Brazil is home to 46,975 native species of algae, fungi, and plants, of which 19,669 are endemic to the country. The data compiled to date suggests that the Atlantic Rainforest might be the most diverse Brazilian domain for all plant groups except gymnosperms, which are most diverse in the Amazon. However, scientific knowledge of Brazilian diversity is still unequally distributed, with the Atlantic Rainforest and the Cerrado being the most intensively sampled and studied biomes in the country. In times of “scientific reductionism”, with botanical and mycological sciences suffering pervasive depreciation in recent decades, the first online Flora of Brazil 2020 significantly enhanced the quality and quantity of taxonomic data available for algae, fungi, and plants from Brazil. This project also made all the information freely available online, providing a firm foundation for future research and for the management, conservation, and sustainable use of the Brazilian funga and flora