▷ Chromatin Regulation of Human & Viral Gene Expression Research Group

Lab presentation

We focus our research on the control of gene expression in human cells by chromatin organization, components and modifications, with a focus on the linker histone. The linker histone in mammals, participating in nucleosome spacing and higher-order chromatin structure, is a family of different histone H1 subtypes, including 7 somatic variants. It is poorly understood why so many H1 variants exist and whether they have particular features relevant to its functionality.

Knock-out experiments have suggested that the different variants are redundant and one isoform can substitute for another, but slowly new reports including ours are suggesting specific roles for the H1 variants, including involvement in specific gene expression regulation, and differential distribution in the human genome.

In a second line of research, we use an HIV promoter model to investigate the influence of chromatin organization at the integration site on HIV expression, with a focus on the role of heterochromatin on the establishment of viral latency, and we search for therapies for reactivation.

Projects

FUNCTIONAL SPECIFICITY OF HUMAN HISTONE H1 VARIANTS AND ROLE IN CANCER

Importance of H1 variants and the effect of their depletion on tumor progression and sensitivity to therapeutic interventions.
Role and specificity of H1 variants in the organization of the genome and the nucleus.
To study the functions of the H1 variants by identifying specific interactions with cellular factors.

The general objective of the present project is to understand why there are up to 7 variants of histone H1 in human somatic cells. Which functional differences exist between them, which occupation of the genome present, and which interactions establish with other nuclear factors or components of chromatin, and whether this depends on the cell type, cell stage, or is related to the cancerous process. The aim of the project is to understand how a structural component of chromatin is involved in the regulation of nuclear processes including the control of gene expression, with implications for proliferation, differentiation and deregulation of the tumor process.

We are an epigenomics laboratory where we use conventional molecular biology techniques to measure gene expression and protein accumulation, high-resolution confocal microscopy, proteomics, genomics (RNAseq, ChIPseq, ATACseq, HiC) and extensive bioinformatics. We use several human cancer cell models including 3D tumoroids/organoids and we plan to use single-cell analysis. We have developed all the tools to investigate the functionality of human H1 variants including specific antibodies and viral vectors for the expression or depletion of H1 variants.

Lab people

Albert Jordan

Research Scientist CSIC

Principal investigator

After graduating in Biology at Autonomous University of Barcelona (UAB) Albert Jordan
went on to do his Ph.D. (1992-95) in the laboratory of Drs Jordi Barbé and Isidre Gibert
at the Dept. Genetics and Microbiology, UAB, where he was a Lecturer afterwards
(1996-98). In the meantime he spent five consecutive summer periods in Dr Peter
Reichard’s laboratory at the Karolinska Institute, Stockholm.

He then moved to San Francisco to undertake his postdoctoral work in the group of
Dr Eric Verdin at the Gladstone Institutes-UCSF (1999-2001), where he became interested
in the role of chromatin in human and viral gene expression control. In 2002 he got a
Ramon y Cajal appointment to join the group of Dr Miguel Beato at CRG (Barcelona) where he
became staff scientist afterwards. Later, in 2008, he got a permanent CSIC position to
start an independent group at IBMB, Dept. Molecular Genomics.

He has been Department director on 2011-13 and 2015-19. In parallel, Dr Jordan has been
appointed coordinator of the Molecular Biology section of the Catalan Society of
Biology (SCB) between 2009-16, coordinator of the Chromatin and Epigenetics section
since 2017, and member of the Directive Committee of SCB (Sections Coordinator,
Secretary) since 2012. Dr Jordan has been awarded several public and private grants,
directed 12 PhD thesis and published more than 50 papers.

Twitter
Coordinator of the group FUNCTIONAL SPECIFICITY AND REGULATION OF HISTONE H1-ESFUREH1

Coordinator of the CHROMATIN and EPIGENETICS section of the CATALAN SOCIETY of BIOLOGY
https://scb.iec.cat/cromatina-i-epigenetica/

Carles Bonet

Director Tècnic

Daniel García

PhD Student

Mónica Salinas

PhD Student

Núria Serna

PhD Student

Pau Homs

Masters Student

Past students

Alberto Bustillos

PhD Student

Andrea Izquierdo

PhD Student

Erik Abner

PhD Student

Lluís Millan

PhD Student

Edurne Gallastegui

PhD Student

Albert Carcereny

JAE Intro grant

Jaione Telleria Zufiaur

Masters Student

Mónica Salinas / personnel hired through aid for the recruitment of Novel research personnel (FI).

Selected publications

View all publications

Fernández-Justel JM, Santa-María C, Martín-Vírgala S, Ramesh S, Ferrera-Lagoa A, Salinas-Pena M, Isoler-Alcaraz J, Maslon MM, Jordan A, Cáceres JF, Gómez M. (2022) Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner. Cell Reports. 40:111329. doi: 10.1016/j.celrep.2022.111329

Serna-Pujol N*, Salinas-Pena M*, Mugianesi F*, Le Dily F, Marti-Renom MA, Jordan A (2022) Coordinated changes in gene expression, H1 variant distribution and genome 3D conformation in response to H1 depletion. Nucleic Acids Research 05 April 2022. doi: 10.1093/nar/gkac226

Ponte I, Andrés M, Jordan A, Roque A (2021) Towards understanding the regulation of histone H1 somatic subtypes with OMICs. Journal of Molecular Biology 433: 166734. doi: 10.1016/j.jmb.2020.166734

Serna-Pujol N, Salinas-Pena M, Mugianesi F, Lopez-Anguita N, Torrent-Llagostera F, Izquierdo-Bouldstridge A, Marti-Renom MA, Jordan A (2021) TADs enriched in histone H1.2 strongly overlap with the B compartment, inaccessible chromatin and AT-rich Giemsa bands. The FEBS Journal 288: 1989-2013. doi: 10.1111/febs.15549

Abner E, Jordan A (2019) HIV ‘shock and kill’ therapy: in need of revision. Antiviral Research 166: 19-34. doi: 10.1016/j.antiviral.2019.03.008

Abner E, Stoszko M, Zeng L, Chen H-C, Izquierdo-Bouldstridge A, Konuma T, Zorita E, Fanunza E, Zhang Q, Mahmoudi T, Zhou M-M, Filion G, Jordan A (2018) A new quinoline BRD4 inhibitor targets a distinct latent HIV-1 reservoir for re-activation from other ‘shock’ drugs. Journal of Virology 2018 Apr 27;92(10). pii: e02056-17. doi: 10.1128/JVI.02056-17

Izquierdo-Bouldstridge A*, Bustillos A*, Bonet-Costa C, Aribau P, Garcia D, Dabad M, Esteve-Codina A, Pascual L, Peiro S, Esteller M, Murtha M, Millán-Ariño Ll, Jordan A (2017) Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Research 45(20): 11622-42. doi: 10.1093/nar/gkx746

Millán-Ariño Ll, Izquierdo-Bouldstridge A, Jordan A (2016) Specificities and genomic distribution of somatic mammalian histone H1 subtypes. BBA Gene Regulatory Mechanisms 1859(3): 510-19. doi: 10.1016/j.bbagrm.2015.10.013

Mayor R*, Izquierdo-Bouldstridge A*, Millán-Ariño Ll, Bustillos A, Sampaio C, Luque N, Jordan A (2015) Genome distribution of replication-independent histone H1 variants shows H1.0 associated with nucleolar domains and H1X associated with RNA polymerase II-enriched regions. Journal of Biological Chemistry 290(12):7474-91. doi: 10.1074/jbc.M114.617324

Millán-Ariño Ll, Islam A, Izquierdo-Bouldstridge A, Mayor R, Terme JM, Luque N, Sancho M, López-Bigas N, Jordan A (2014) Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2. Nucleic Acids Research 42:4474-4493. doi: 10.1093/nar/gku079

Gallastegui E, Marshall B, Vidal D, Sanchez-Duffhues G, Collado JA, Alvarez-Fernández C, Luque N, Terme JM, Gatell JM, Sánchez-Palomino S, Muñoz E, Mestres J, Verdin E, Jordan A (2012) Combination of biological screening in a cellular model of viral latency with virtual screening identifies novel compounds that reactivate HIV-1. Journal of Virology 86(7):3795-3808. doi: 10.1128/JVI.05972-11

Terme JM*, Sesé B*, Millán-Ariño L, Mayor R, Izpisua-Belmonte JC, Barrero MJ, Jordan A (2011) Histone H1 variants are differentially expressed and incorporated into chromatin during differentiation and reprogramming to pluripotency. Journal of Biological Chemistry 286(41):35347-57. doi: 10.1074/jbc.M111.281923

Gallastegui E, Millán-Zambrano G, Terme JM, Chávez S, Jordan A (2011) Chromatin reassembly factors are involved in transcriptional interference promoting HIV latency. Journal of Virology 85(7):3187-202. doi: 10.1128/JVI.01920-10

Sancho M, Diani E, Beato M, Jordan A (2008) Depletion of human histone H1 variants uncovers specific roles in gene expression and cell growth. PLOS Genetics 2008 Oct;4(10):e1000227. doi: 10.1371/journal.pgen.1000227

Subtil-Rodríguez A, Millán-Ariño L, Quiles I, Ballaré C, Beato M, Jordan A (2008) Progesterone induction of 11ß-hydroxysteroid dehydrogenase type 2 promoter in breast cancer cells involves coordinated recruitment of STAT5A and PR to a distal enhancer and polymerase tracking. Molecular and Cellular Biology 28: 3830-3849. doi: 10.1128/MCB.01217-07

Vicent GP, Ballaré C, Nacht AS, Clausell J, Subtil-Rodríguez A, Quiles I, Jordan A, Beato M. (2006) Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Molecular Cell 24: 367-381. doi: 10.1016/j.molcel.2006.10.011

Larsson KM, Jordan A, Eliasson R, Reichard P, Logan DT, Nordlund P (2004) Structural mechanisms of allosteric substrate specificity regulation in a ribonucleotide reductase. Nature Structure and Molecular Biology 11: 1142-1149. doi: 10.1038/nsmb838

Jordan A, Bisgrove D, Verdin E. (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. The EMBO Journal 22: 1868-1877. doi: 10.1093/emboj/cdg188

Jordan A, Defechereux P, Verdin E (2001) The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivator. The EMBO Journal 20: 1726-1738. doi: 10.1093/emboj/20.7.1726

Jordan A, Reichard P. (1998) Ribonucleotide reductases. Annual Reviews of Biochemistry 67: 71-98. doi: 10.1146/annurev.biochem.67.1.71

Jordan A, Torrents E, Jeanthon C, Eliasson R, Hellman U, Wernstedt C, Barbé J, Gibert I, Reichard, P. (1997) B12-dependent ribonucleotide reductases from deeply rooted eubacteria are stucturally related to the aerobic enzyme from Escherichia coli. Proceedings of the National Academy of Sciences USA 94: 13487-13492. doi: 10.1073/pnas.94.25.13487

Jordan A, Pontis E, Atta M, Krrok M, Gibert I, Barbé J, Reichard P. (1994) A second class I ribonucleotide reductase in Enterobacteriaceae: characterization of the Salmonella typhimurium enzyme. Proceedings of the National Academy of Sciences USA 91: 12892-12896. doi: 10.1073/pnas.91.26.12892

ORCID: 0000-0002-3970-8693 (Albert Jordan)

For a complete list of A. Jordan publications, search PubMed for:

(jordan a and roque a ) or (jordan a and salinas-pena M ) or (jordan a and serna-pujol n) or (jordan a and bonet-costa c) or (jordan a and izquierdo-bouldstridge a) or (jordan a and bartrons r) or (jordan a and terme jm) or (jordan a and chavez s) or (jordan a and beato m) or (jordan a and verdin e) or (jordan a and reichard p) or (jordan a and gibert i) or (jordan a and uhlin u) or (jordan a and eklund h) or (valles aj) or (jordan a and biochim biophys acta) or (jordan a and bachs o) or (jordan a and langley e) or (jordan a and szabo g) or (jordan a and abner e)

View all publications

All publications

View selected publications

Imre L*, Firouzi Niaki E*, Bosire R, Nanasi Jr. P, Nagy P, Bacso Z, Hamidova N, Pommier Y, Jordan A, Szabo G (2022) Nucleosome destabilization by polyamines. Archives of Biochemistry and Biophysics. 05 April 2022. doi.org/10.1016/j.abb.2022.109184

Abner E, Jordan A (2019) HIV ‘shock and kill’ therapy: in need of revision. Antiviral Research 166: 19-34. doi: 10.1016/j.antiviral.2019.03.008

Salmerón-Hernández A, Noriega-Reyes MY, Jordan A, Baranda-Avila N, Langley E (2019) BCAS2 Enhances Carcinogenic Effects of Estrogen Receptor Alpha in Breast Cancer Cells. International Journal of Molecular Sciences Feb 22;20(4). pii: E966. doi: 10.3390/ijms20040966

Carbonell A, Fueyo R, Izquierdo-Bouldstridge A, Moreta C, Jordan A (2018) Epigenetic mechanisms in health and disease: BCEC 2017. Epigenetics 13(3): 331-341. doi: 10.1080/15592294.2018.1434391

Perearnau A, Orlando S, Islam A, Gallastegui E, Martínez J, Jordan A, Bigas A, Aligué R, Pujol MJ, Bachs O (2017) p27Kip1, PCAF and PAX5 cooperate in the transcriptional regulation of specific target genes. Nucleic Acids Research 45(9):5086-99. doi: 10.1093/nar/gkx075

Castaño J, Morera C, Sesé B, Boue S, Bonet-Costa C, Marti M, Roque A, Jordan A, Barrero MJ (2016) SETD7 regulates the differentiation of human embryonic stem cells. PLOS One doi: 10.1371/journal.pone.0149502.

Jordan A (2016) Editorial-Histone H1 in gene expression and development. BBA Gene Regulatory Mechanisms 1859(3): 429-30. doi: 10.1016/j.bbagrm.2016.01.001

Noriega-Reyes MY, Rivas-Torres MA, Oñate-Ocaña LF, Jordan-Vallés A, Baranda-Avila N, Langley E (2015) Novel role for PINX1 as a coregulator of nuclear hormone receptors. Molecular and Cellular Endocrinology 414: 9-18. doi: 10.1016/j.mce.2015.07.011

Terme JM, Millán-Ariño Ll, Mayor R, Luque N, Izquierdo-Bouldstridge A, Bustillos A, Sampaio C, Canes J, Font I, Sima N, Sancho M, Torrente L, Forcales S, Roque A, Suau P, Jordan A (2014) Dynamics and dispensability of variant-specific histone H1 Lys-26/Ser-27 and Thr-165 post-translational modifications. FEBS Letters 588(14):2353-62. doi: 10.1016/j.febslet.2014.05.035

Novellasdemunt L, Obach M, Millán-Ariño Ll, Manzano A, Ventura F, Rosa JL, Jordan A, Navarro-Sabate A, Bartrons R (2012) Progestins activate 6-Phosphofructo-2-kinase/Fructose-2,6-Bisphosphatase (PFKFB3) in breast cancer cells. Biochemical Journal 442(2):345-56. doi: 10.1042/bj20111418

Terme JM, Calvignac S, Duc Dodon M, Gazzolo L, Jordan A (2009) E box motifs as mediators of proviral latency of human retroviruses. Retrovirology 6: 81. doi: 10.1186/1742-4690-6-81

Quiles I, Millán-Ariño L, Subtil-Rodríguez A, Miñana B, Spinedi N, Ballaré C, Beato M, Jordan A (2009) Mutational analysis of progesterone receptor functional domains in stable cell lines delineates sets of genes regulated by different mechanisms. Molecular Endocrinology 23: 809-26. doi: 10.1210/me.2008-0454

Vanti M*, Gallastegui E*, Respaldiza I, Rodríguez-Gil A, Gómez-Herreros F, Jimeno-González S, Jordan A and Chávez S (2009) Yeast genetic analysis reveals the involvement of chromatin reassembly factors in repressing HIV-1 basal transcription. PLOS Genetics 2009 Jan;5(1):e1000339. doi: 10.1371/journal.pgen.1000339

Vicent GP, Ballaré C, Nacht AS, Clausell J, Subtil-Rodríguez A, Quiles I, Jordan A, Beato M (2008) Convergence on chromatin of non-genomic and genomic pathways of hormone signaling. Journal of Steroid Biochemistry and Molecular Biology 109: 344-349. doi: 10.1016/j.jsbmb.2008.03.015

Jordan A, Bisgrove D, Verdin E. (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. The EMBO Journal 22: 1868-1877. doi: 10.1093/emboj/cdg188

Pion M, Jordan A, Biancotto A, Dequiedt F, Gondois-Rey F, Rondeau S, Vigne R, Hejnar J, Verdin E, Hirsch I (2003) Transcriptional suppression of in vitro-integrated human immunodeficiency virus type 1 does not correlate with proviral DNA methylation. Journal of Virology 77: 4025-4032. doi: 10.1128/jvi.77.7.4025-4032.2003

Jordan A, Torrents E, Sala I, Hellman U, Gibert I, Reichard, P (1999) Ribonucleotide reduction in Pseudomonas species: simultaneous presence of active enzymes from different classes. Journal of Bacteriology 181: 3974-3980. doi: 10.1128/2Fjb.181.13.3974-3980.1999

Eliasson R, Pontis E, Jordan A, Reichard P (1999) Allosteric control of three B12-dependent (class II) ribonucleotide reductases. Implication for the evolution of ribonucleotide reduction. Journal of Biological Chemistry 274: 7182-7189. doi: 10.1074/jbc.274.11.7182

Jordan A, Reichard P. (1998) Ribonucleotide reductases. Annual Reviews of Biochemistry 67: 71-98. doi: 10.1146/annurev.biochem.67.1.71

Fieschi F, Torrents E, Toulokhonova L, Jordan A, Hellman U, Gibert I, Barbé J, Karlsson M, Sjöberg B-M. (1998) The manganese-containing ribonucleotide reductase of Corynebacterium ammoniagenes is a class Ib enzyme. Journal of Biological Chemistry 273: 4329-4337. doi: 10.1074/jbc.273.8.4329

Jordan A, Åslund F, Pontis E, Reichard P, Holmgren A. (1997) Characterization of E. coli NrdH: a glutaredoxin-like protein with thioredoxin-like activity profile. Journal of Biological Chemistry 2: 18044-18050. doi: 10.1074/jbc.272.29.18044

Eliasson R, Pontis E, Jordan A, Reichard P. (1996) Allosteric regulation of the third ribonucleotide reductase (NrdEF enzyme) from Enterobacteriaceae. Journal of Biological Chemistry 271: 26582-26587. doi: 10.1074/jbc.271.43.26582

Jordan A, Pontis E, Åslund F, Hellman U, Gibert I, Reichard P. (1996) The ribonucleotide reductase system of Lactococcus lactis. Characterization of an NrdEF-enzyme and a new electron transport protein. Journal of Biological Chemistry 27: 8779-8785. doi: 10.1074/jbc.271.15.8779

Jordan A, Aragall E, Gibert I, Barbé J. (1996) Promoter identification and expression analysis of Salmonella typhimurium and Escherichia coli nrdEF operons encoding one of two class I ribonucleotide reductases present in both bacteria. Molecular Microbiology 19:777-790. doi: 10.1046/j.1365-2958.1996.424950.x

Jordan A, Gibert I, Barbé J. (1994) Cloning and sequencing of the genes from S. typhimurium encoding a new bacterial ribonucleotide reductase. Journal of Bacteriology 176: 3420-3427. doi: 10.1128/jb.176.11.3420-3427.1994

ORCID: 0000-0002-3970-8693 (Albert Jordan)

For a complete list of A. Jordan publications, search PubMed for:

View selected publications

covers-chromatin-regulation-of-human-and-viral-gene-expression

Project funding

Functional specificity of human histone H1 variants and role in cancer.

AGENCY: Ministerio de Ciencia e Innovación – Plan Nacional BFU
PERIOD: 2021 – 2024.
IP: Albert Jordan Vallès

Proyecto PID2020-112783GB-C21 financiado por:

Especificidad funcional de las variantes de la histona H1 humana:

AGENCY: Ministerio de Ciencia e Innovación – Plan Nacional BFU
PERIOD: 2018 – 2020
IP: Albert Jordan Vallès

Proyecto BFU2017-82805-C2-1-P financiado por:

Especificidad funcional de las variantes de la histona H1 humana.

AGENCY: Ministerio de Ciencia e Innovación – Plan Nacional BFU
PERIOD: 2015 – 2017
IP: Albert Jordan Vallès

Especificidad funcional de las variantes de la histona H1 humanas:

AGENCY: Ministerio de Ciencia e Innovación – Plan Nacional BFU
PERIOD: 2012 – 2014
IP: Albert Jordan Vallès

Determinantes genómicos del estado latente del VIH-1 y estrategias terapéuticas:

AGENCY: FIPSE
PERIOD: 2011 – 2013
IP: Albert Jordan Vallès

Estrategias terapéuticas para la reactivación del Virus de la Immunodeficiencia Humana en células latentes:

AGENCY: Fundación Eugenio Rodríguez Pascual
PERIOD: 2011
IP: Albert Jordan Vallès

Genómica estructural y aplicada:

AGENCY: AGAUR-DURSI – Grupos reconocidos
PERIOD: 2009 – 2013
IP: Joaquim Roca / Marian Martínez Balbas / Xavier de la Cruz / Albert Jordan

Especificidad de las variantes de la histona H1 humanas en la estructura de la cromatina, expresión génica y proliferación:

AGENCY: Ministerio de Ciencia e Innovación – Plan Nacional BFU
PERIOD: 2009 – 2011
IP: Albert Jordan Vallès

Reactivación del VIH en células T latentemente infectadas in vitro e in vivo:

AGENCY: FIPSE
PERIOD: 2006 – 2009
IP: Albert Jordan Vallès

Latencia del VIH. Estudio del mecanismo molecular y búsqueda de dianas para la reactivación:

AGENCY Instituto de Salud Carlos III – Fondo de Investigación Sanitaria
PERIOD: 2006 – 2008
IP: Albert Jordan Vallès

Regulación transcripcional y reorganización de la cromatina en los promotores pS2, 11 beta-HSD y MMTV en células de cáncer de mama en respuesta a hormonas esteroideas:

AGENCY: Ministerio de Ciencia y Tecnología – Plan Nacional SAF
PERIOD: 2002 – 2005
IP: Albert Jordan Vallès

Vacancies/Jobs

Candidates, send CV and an introductory letter (experience, references, motivation…) by email to albert.jordan@ibmb.csic.es

Pre- and post-doc candidates Chromatin regulation of human and viral gene expression

June 21 2020

Pre- and post-doc candidates with an outstanding CV to apply to competitive fellowships will be always…

Lab corner

COORDINATED CHANGES IN GENE EXPRESSION, H1 VARIANT DISTRIBUTION AND GENOME 3D CONFORMATION IN RESPONSE TO H1 DEPLETION

Researchers of the IBMB have investigated for the first time the genomic distribution of five histone H1 variants in a human cancer cell line and the consequences of H1 depletion on the 3D conformation of the genome, which will help to better understand the function of this structural component of chromatin. Up to seven members of the histone H1 family may contribute to chromatin compaction and its regulation in human somatic cells. In breast cancer cells, knock-down of multiple H1 variants deregulates many genes, promotes the appearance of genome-wide accessibility sites and triggers an interferon response via activation of heterochromatic repeats. However, how these changes in the expression profile relate to the re-distribution of H1 variants as well as to genome conformational changes have not been yet studied. Here, we combined ChIP-seq of five endogenous H1 variants with Chromosome Conformation Capture analysis in wild-type and H1.2/H1.4 knock-down T47D cells. The results indicate that H1 variants coexist in the genome in two large groups depending on the local GC content and that their distribution is robust with respect to H1 depletion. Despite the small changes in H1 variants distribution, knock-down of H1 translated into more isolated but de-compacted chromatin structures at the scale of topologically associating domains (TADs). Such changes in TAD structure correlated with a coordinated gene expression response of their resident genes. This is the first report describing simultaneous profiling of five endogenous H1 variants and giving functional evidence of genome topology alterations upon H1 depletion in human cancer cells.

Serna-Pujol N*, Salinas-Pena M*, Mugianesi F*, Le Dily F, Marti-Renom MA, Jordan A (2022) Coordinated changes in gene expression, H1 variant distribution and genome 3D conformation in response to H1 depletion. Nucleic Acids Research 05 April 2022. https://doi.org/10.1093/nar/gkac226

TADS ENRICHED IN HISTONE H1.2 STRONGLY OVERLAP WITH THE B COMPARTMENT, INACCESSIBLE CHROMATIN AND AT-RICH GIEMSA BANDS

An epigenetic characterization of Giemsa bands (G bands) performed by researchers of the IBMB has revealed their utility as epigenetic units to investigate the differential distribution of linker histones. Giemsa staining of metaphase chromosomes results in a characteristic banding useful for identification of chromosomes and its alterations. Staining of G positive bands decreases with GC content. High GC bands are enriched in active histone marks, RNA polymerase II and SINEs, and associate to gene richness, gene expression and early replication. Histone H1 variants also 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. Besides, Hi-C analysis has shown that TADs with high H1.2/H1X ratio strongly overlap with B compartment, late replicating and inaccessible chromatin, and low GC bands. Serna et al. 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.

Serna-Pujol N, Salinas-Pena M, Mugianesi F, Lopez-Anguita N, Torrent-Llagostera F, Izquierdo-Bouldstridge A, Marti-Renom MA, Jordan A (2020) TADs enriched in histone H1.2 strongly overlap with the B compartment, inaccessible chromatin and AT-rich Giemsa bands. FEBS Journal doi: 10.1111/febs.15549.

Download Figure 4 correctly printed.

HIV ‘SHOCK AND KILL’ THERAPY: IN NEED OF REVISION

The implementation of antiretroviral therapy 23 years ago has rendered HIV infection clinically manageable. However, the disease remains incurable, since it establishes latent proviral reservoirs, which in turn can stochastically begin reproducing viral particles throughout the patient’s lifetime. Viral latency itself depends in large part on the silencing environment of the infected host cell, which can be chemically manipulated. “Shock and kill” therapy intends to reverse proviral quiescence by inducing transcription with pharmaceuticals and allowing a combination of antiretroviral therapy, host immune clearance and HIV-cytolysis to remove latently infected cells, leading to a complete cure. Over 160 compounds functioning as latency-reversing agents (LRAs) have been identified to date, but none of the candidates has yet led to a promising functional cure. In this review we describe the variety of existing classes of LRAs, discuss their current drawbacks and highlight the potential for combinatorial “shocktail” therapies for potent proviral reactivation.

Abner E, Jordan A (2019) HIV ‘shock and kill’ therapy: in need of revision. Antiviral Research 166: 19-34. doi: 10.1016/j.antiviral.2019.03.008.

A NEW QUINOLINE BRD4 INHIBITOR TARGETS A DISTINCT LATENT HIV-1 RESERVOIR FOR RE- ACTIVATION FROM OTHER ‘SHOCK’ DRUGS

Researchers of the IBMB have shown that a previously identified Human Immunodeficiency Virus (HIV) latency-reversing agent (MMQO) acts as a bromodomain inhibitor. Despite of very different chemical structures, MMQO mimics the action of JQ1, a well-known bromodomain inhibitor, and binds to the bromodomain and extraterminal domain (BET) family protein BRD4. Utilizing barcoded HIV-1minigenomes, we demonstrate that PKC pathway activators, HDAC and bromodomain inhibitors all target different subsets of proviral integrations. Considering the fundamental differences of these compounds and the synergies displayed between them, we propose that the field should concentrate on investigating the development of combinatory “shock” cocktail therapies for an improved reservoir reactivation aiming to eradicate the latent functional proportion of HIV-1 proviruses in a patient.

HISTONE H1 DEPLETION TRIGGERS AN INTERFERON RESPONSE IN CANCER CELLS VIA ACTIVATION OF HETEROCHROMATIC REPEATS

Researchers of the IBMB have shown that simultaneous depletion of particular histone H1 variants in human breast cancer cells triggers the cellular interferon response, originally designed to fight against invading pathogen-associated nucleic acids such as DNA or RNA viruses. They have shown that this is due to the derepression of heterochromatic non-coding RNAs such as satellites and endogenous retroviruses, which may be naturally repressed with the participation of particular histone H1 subtypes such as H1.2 and H1.4.

Project gallery

COORDINATED CHANGES IN GENE EXPRESSION, H1 VARIANT DISTRIBUTION AND GENOME 3D CONFORMATION IN RESPONSE TO H1 DEPLETION (Nucleic Acids Research 2022)

HISTONE H1 DEPLETION TRIGGERS AN INTERFERON RESPONSE IN CANCER CELLS VIA ACTIVATION OF HETEROCHROMATIC REPEATS (Nucleic Acids Research 2017)

A NEW QUINOLINE BRD4 INHIBITOR TARGETS A DISTINCT LATENT HIV-1 RESERVOIR FOR REACTIVATION FROM OTHER ‘SHOCK’ DRUGS (Journal of Virology 2018)

HIV ‘SHOCK AND KILL’ THERAPY: IN NEED OF REVISION (Antiviral Research 2019)

TADS ENRICHED IN HISTONE H1.2 STRONGLY OVERLAP WITH THE B COMPARTMENT, INACCESSIBLE CHROMATIN AND AT-RICH GIEMSA BANDS (FEBS Journal 2020)

Contact

Albert Jordan

Research Scientist CSIC