• Epigenetic mechanisms (post-translational modifications of histones, long noncoding RNAs, nuclear architecture and remodeling complexes) that regulate gene expression in Plasmodium falciparum

• Epigenetic mechanisms involved in the development of pancreatic cancer

• Identification of epigenetic biomarkers for the diagnosis of pancreatic cancer.

• Epigenetic mechanisms involved in the maintenance of pancreatic cancer stem cells (microRNAs, histone variants, and DNA hydroxymethylation)

• Development of epi-drugs against pancreatic cancer.

Collaborations

• Dr. Artur Scherf. Institute Pasteur. Unité des Interaction Hote-Parasite. Paris     Francia.

• Dr. Félix Recillas Targa, Instituto de Fisiología Celular. Universidad Nacional Autónoma de México. México, D. F.

• Dra. Nancy Guillén Institute Pasteur, Unité des InteractionHote-Parasite. Paris Francia.

• Dr. Santiago Martínez Calvillo. Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México.

• Dr. Miguel Ángel Vargas Mejía. Departamento de Biomedicina Molecular CINVESTAV-IPN. Unidad Zacatenco

• Dr. Roberto Herrera Goepfer. Departamento de Patología, Instituto Nacional de Cancerología, Ciudad de México

• Dra. Hernández-Montes Georgina. Coordinación de la Investigación Científica, Red de Apoyo a la Investigación. Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México.

Publications

• Research articles published indexed: 59

• Extensive Research Articles: 4

• Disclosure Articles 4

• National book chapters: 4

• International book chapters: 4

• Number of citations to my publications: 2811

Thesis direction

• Doctorate: 9.

• Mastery: 32.

• Bachelor's Degree: 2

Congresses: 93

Honours and Awards

• Gabino Barreda Medal 1992 PhD from the National Autonomous University of Mexico.

• 1992 Honorable Mention in the doctoral degree examination. National Autonomous University of Mexico.

• 1993 Award, Lola and Igo Flisser for the best doctoral thesis in Parasitology.

• 1994 Scholarship, Foundation pour la Recherche Médicale.

• 1995 Scholarship, Pasteur-Weizmann.

• 1996 Scholarship, Foundation pour la Recherche Médicale.

• 2006 Award, Lola and Igo Flisser for the best doctoral thesis in Parasitology my PhD student Omar Khayan Ruvalcaba.

• 2006 Honorable Mention, Lola and Igo Flisser Award for the best doctoral thesis in Parasitology my PhD student Dvorak Montiel Condado.

Grants

International

• European Union for Research and Technical Development (1999-2002) "Adhesion of Plasmodium falciparum infected erythrocytes to host glycosaminoglycans and sequestration elimination studies in Saimiri monkeys". For three years from March 9, 1998.

• Bilateral Mexico-France Project ANR-CONACyT "Paractin: Impact of actin and actin-related proteins in human parasitic infections". For three years from July 2011 to July 2014.

National

• CONACyT Mèxico (1998-2000) "Molecular and Cellular Study of the Plasmodium falciparum var-CSA gene and its relationship with Maternal Malaria".

• CONACyT México (2001-2004) “Isolation and characterization of the var-2CSA promoter from Plasmodium falciparum gene”.

• CONACyT Mexico (2005-2008). "TATA-binding protein factors associated with TBP"

• CONACyT México (June 2008 to June 2011). "Identification of nuclear factors that interact with the Rep20 subtelomeric region in Plasmodium falciparum".

• CONACyT (Mexico) January 2013 to January 2016. "Processing of the amino terminal end of histone H3 in P. falciparum: a probable epigenetic mechanism"

• FONSEC SSA / IMSS / ISSTE Fondo Salud. To develop the project entitled "Identification of epigenetic biomarkers present in the bloodstream of patients with pancreatic cancer, as a diagnostic test." April 2017- July 2021.

• Ávila-López PA., Guerrero G., Nuñez-Martínez HN., Peralta-Alvarez CA., Hernández-Montes G., Álvarez-Hilario LG., Herrera-Goepfert R., Albores-Saavedra J, Villegas-Sepúlveda N, Cedillo-Barrón L., Vargas M., Recillas-Targa F. and Hernández-Rivas R. H2A.Z overexpression suppresses senescence and chemosensitivity in pancreatic ductal adenocarcinoma. Oncogene. Feb 24.doi: 10.1038/s41388-021-01664-1.Factor de Impacto 7.971.

• Lozano-Amado D, Ávila-López PA, Hernández-Montes G, Briseño-Díaz P, Vargas M, Lopez-Rubio JJ, Carrero JC, Hernández-Rivas R. (2020) A class I histone deacetylase is implicated in the encystation of Entamoeba invadens. Int J Parasitol. 50(12):1011-1022. doi: 10.1016/j.ijpara.2020.05.014. Factor de impacto 3.872.

• Pérez-Olais JH, Ruiz-Jiménez F, Calderón-García EJ, De Jesús-González LA, Hernández-Rivas R, Del Angel RM (2019). The activity of Aurora kinase B is required for dengue virus release. Virus Res 274:197777. doi: 10.1016/j.virusres.2019.197777. Factor de Impacto 2.736.

• Herrera-Solorio AM, Vembar SS, MacPherson CR, Lozano-Amado D, Meza GR, Xoconostle-Cazares B, Martins RM, Chen P, Vargas M, Scherf A, Hernández-Rivas R. (2019). Clipped histone H3 is integrated into nucleosomes of DNA replication genes in the human malaria parasite Plasmodium falciparum. EMBO Rep. 20(4). pii: e46331. doi: 10.15252/embr.20184633. Factor de Impacto 7.497.

• Casique-Aguirre D, Briseño-Díaz P, García-Gutiérrez P, la Rosa CHG, Quintero-Barceinas RS, Rojo-Domínguez A, Vergara I, Medina LA, Correa-Basurto J, Bello M, Hernández-Rivas R, Del RocioThompson-Bonilla M, Vargas M. (2018). KRas4B-PDE6d complex stabilization by small molecules obtained by virtual screening affects Ras signaling in pancreatic cancer. BMC Cancer. 18(1):1299. doi: 10.1186/s12885-018-5142-7. Factor de Impacto 3.150.

• Cruz-Nova P, Schnoor M, Correa-Basurto J, Bello M, Briseño-Diaz P, Rojo-Domínguez A, Ortiz-Mendoza CM, Guerrero-Aguirre J, García-Vázquez FJ, Hernández-Rivas R, Thompson-Bonilla MDR, Vargas M. (2018). The small organic molecule C19 binds and strengthens the KRAS4b-PDEd complex and inhibits growth of colorectal cancer cells in vitro and in vivo. BMC Cancer. 1;18 (1):1056. doi: 10.1186/s12885-018-4968-3. Factor de Impacto 3.150.

• Sierra-Miranda M, Vembar SS, Delgadillo DM, Ávila-López PA, Herrera-Solorio AM, Lozano Amado D, Vargas M, Hernandez-Rivas R. (2017). PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds to Plasmodium falciparum telomeres. Cell Microbiol. 19(9). doi: 10.1111/cmi.12742. Epub 2017. doi: 10.1111/cmi.12742. Factor de Impacto 4.3.

• Romero-Meza G, Ramírez DE, Florencio-Martínez LE, Román-Carraro FC, Manning-Cela R, Hernández-Rivas R, Martínez-Calvillo S. (2017). Maf1 is a negative regulator of transcription in Trypanosoma brucei. Mol. Microbiol. 103(3):452-468. doi: 10.1111/mmi.13568.Factor de impacto 3.816.

• De la Rocha C, Pérez-Mojica JE, León SZ, Cervantes-Paz B, Tristán-Flores FE, Rodríguez-Ríos D, Molina-Torres J, Ramírez-Chávez E, Alvarado-Caudillo Y, Carmona FJ, Esteller M, Hernández-Rivas R, Wrobel K, Wrobel K, Zaina S, Lund G. (2016). Associations between whole peripheral blood fatty acids and DNA methylation in humans. Sci Rep. 16(6): 25867. doi: 10.1038/srep25867. Factor de impacto 3.998.

• Lozano-Amado D, Herrera-Solorio AM, Valdés J, Alemán-Lazarini L, Almaraz-Barrera M. de J, Luna-Rivera E, Vargas M, Hernández-Rivas R. Identification of repressive and active epigenetic marks and nuclear bodies in Entamoeba histolytica. Parasites and Vectors. 2016 148(9):19. doi: 10.1186/s13071-016-1298-7. Factor de Impacto 3.430.

Rosaura Hernández Rivas (Head group)

• Héctor Iván Saldivar Cerón. CINVESTAV PhD student.
• Eustolia Isabel Quintanilla Mora. CINVESTAV PhD student.
• Leonardo Martínez Cisneros. CINVESTAV Master student.
• Eric Genaro Salmerón Bárcenas. Research assistant.

Our group has found that chromatin architecture plays a relevant role in regulating the expression of var genes, which in Plasmodium falciparum encode the PfEMP-1 protein. This protein is involved in cytoadherence and antigenic variation, two key events in the pathogenicity of Plasmodium. We also found that telomeric heterochromatin not only has a structural role but can regulate the expression of virulence genes by extending telomeric heterochromatin towards virulence genes (which in this parasite are adjacent to telomeres), which leads to transcriptional (reversible) repression of these genes by a mechanism known as the Telomere Position Effect or TPE. We also show that the telomeres of this parasite are transcribed and that these long non-coding RNA transcripts probably participate in regulating gene expression. Additionally, we have found that Plasmodium histone H3 is processed in a specific stage and that this short version of histone H3 participates in regulating the expression of genes involved in replication. Therefore, we propose that histone H3 proteolysis is another epigenetic mechanism used by the parasite to introduce changes in the chromatin architecture.

Recently, we have started a line of research focused on the study of pancreatic cancer at the epigenetic level. We chose to study pancreatic ductal adenocarcinoma (PDAC), because it is the most common pancreatic cancer, which is an infiltrative neoplasm, almost always fatal, refractory to conventional treatments and, consequently, has a survival rate of only five years in 8% of patients and a mortality rate of up to 95%. In addition, patients rarely have symptoms. Regarding its treatment, gemcitabine (a pyrimidine analog) has been the chemotherapeutic strategy of first choice to combat ACDP for many years (86). However, this chemotherapy has proven to be effective in only 23.8% of PDCA cases, mainly due to the dense tumor stroma that leads to a poor diffusion of the drug coupled with the subsequent development of chemoresistance to this drug. Cancer stem cells (CTC), present in tumor tissue, play critical roles in resistance to cancer treatment and are responsible for metastasis in various human malignant tumors, including PDAC. CTCs are immortal tumor cells found in only 1% of the cells that make up the tumor mass and have the ability to self-renew, produce differentiated progeny, form tumors in mice, and form non-adherent spheroids called tumor spheres in vitro. So then, it is clear that to have a substantial impact on pancreatic cancer, it is necessary to eradicate pancreatic stem cells (paCTC). In this sense, we have found that reducing the levels of H2A.Z in pancreatic tumor cells decreases the amount of cancer stem cells 10 times. Therefore, if the role that H2A.Z has in the maintenance of pancreatic progenitor cells is corroborated, this histone could be considered as a therapeutic target against PDAC, and used for the development of an epi-drug.

Methodologies

• Chromatin immunoprecipitation (DNA-ChIP)
• DNA and RNA EMSA assays
• Northwestern and Southwestern
• RNA / DNA oligonucleotide pulldown
• In situ hybridization assays by using DNA or RNA probes (FISH –RNA / DNA)
• Run-on
• Cloning into yeast artificial chromosomes (YAC)
• Short hairpin technology
• Cell lines transfection
• Cas9/CRISPR system
• Flow cytometry
• Immunoprecipitation and Co-Immunoprecipitation assays
• FISH

The ncRNAs define a novel subdomain in the P. falciparum nucleus. (A) RNA-FISH signals are shown in red, and DNA-FISH signals are shown in green (TARE-6). The signals of the TARE-6 ncRNA and telomeric DNA do not co-localize in ring stages, but in the late-schizont stage some telomere clusters are transcribed and co-localize with TARE-6 ncRNA probe. (B) P. falciparum nucleus present a complex nuclear architecture with several subcompartments localized in the nuclear periphery as are: telomeric clusters, var gene expression site, nucleolus and non-coding RNA compartment. (C) RNA-FISH signals are shown in red (TARE-6), and 28S rDNA DNA-FISH signals are ingreen. The signals from 28S rDNA and the non-coding TARE-6 transcript do not co-localize. (D) Two-color RNA-FISH of a var2CSA RNA probe (green) and TARE-6 ss ncRNA transcripts (red) for ring stage parasites (FCR3-CSA parasite population). The signals from the var2CSA transcripts and the TARE-6 ncRNAs do not co-localize. In all images, nuclear DNA was stained with DAPI (blue). Scale bars: 1 _m for the ring and schizont stages. 70 nuclei were analyzed from two independent experiments.