Epigenetic control of cellular identity and function in human disorders

Epigenetic dysregulation in rare genetic diseases

DNA methylation and other epigenetic modifiers are main players in the establishment and maintenance of cellular homeostasis. Genetic mutations in the de novo DNA methyltransferase B (DNMT3B) cause the main form of the rare genetic Immunodeficiency, Centromere instability and Facial anomalies syndrome (ICF syndrome). This syndrome is representative of a group of epigenetic immunodeficiencies including genetic diseases caused by mutations in epigenetic modifiers determining the impairment of the immunological response. This group also includes the Kabuki syndrome that is due to genetic mutations in KMT2D and KMD6 genes that are involved in histone methylation modifications. Genetic alterations in epigenetic modifiers are also involved in the predisposition to more common immunodeficiencies (CVID).

Our scientific interest is:

1. a) deciphering the fine molecular mechanisms linking the genetic defects in DNMT3B gene and their pleiotropic effects determining the ICF syndrome phenotype;
2. b) investigating how the aberrant DNA/histone methylation contribute to the phenotypic anomalies in hematopoietic differentiation through comparative studies in ICF and Kabuki syndrome cell models

Our study model are iPSC cell lines obtained through the reprogramming of CD34+ cells and fibroblast of patients. We utilize iPSCs to study the early phase of hematopoietic differentiation in which the disease causative mutations exert their main effect. Targeted and “omic” technologies allow a fine molecular dissection of the patient iPSCs and their derivatives in hematopoietic differentiation experiments.

Epigenetic dysregulation and genomic instability in cancer

Perturbations in the DNA methylation machinery constitute one of the mechanisms inducing and prompting cancer. Hypo and hyper-methylation at different levels contribute to reshaping the tumoral cells transcriptomic including the large non-coding component. The finely tuned expression of genes and isoforms is altered by the activation/repression of regulative sequences.

DNMT3B is known to be involved in these regulative processes. Our interest is to explore these mechanisms in blood and solid tumors.

1. Pisapia L, Terreri S, Barba P, Mastroianni M, Donnini M, Mercadante V, Palmieri A, Verze P, Mirone V, Altieri V, Califano G, Liguori GL, Strazzullo M*, Cimmino A, Del Pozzo G. Role of PA2G4P4 pseudogene in bladder cancer tumorigenesis. Biology (Basel). 2020 Mar 31;9(4):66 *co-corresponding author.
2. Spagnuolo MS, Pallottini V, Mazzoli A, Iannotta L, Tonini C, Morone B, Ståhlman M, Crescenzo R, Strazzullo M, Iossa S, Cigliano L. A Short-Term Western Diet Impairs Cholesterol Homeostasis and Key Players of Beta Amyloid Metabolism in Brain of Middle Aged Rats. Mol Nutr Food Res. 2020 Jun 24:e2000541
3. Pisapia L, Hamilton RS, Farina F, D'Agostino V, Barba P, Strazzullo M, Provenzani A, Gianfrani C, Del Pozzo G. Tristetraprolin/ZFP36 Regulates the Turnover of Autoimmune-Associated HLA-DQ mRNAs. Cells. 2019 Dec 4;8(12):1570.
4. Pisapia L, Cerillo I, Farina F, Zimbardo A, Barba P, Orefice G, Gianfrani C, Strazzullo M, Del Pozzo G. The HLA-DRB1 risk alleles for multiple sclerosis are differentially expressed in blood cells of patients from Southern Italy. Int J Immunogenet 2019 Dec;46(6):479-484.
5. Gagliardi M, Strazzullo M*, Matarazzo MR. DNMT3B Functions: Novel Insights From Human Disease. Front Cell Dev Biol. 2018 Oct 22;6:140. doi: 10.3389/fcell.2018.00140 *co-corresponding author.
6. Gianfrani, C, Pisapia L, Picascia S, Strazzullo, M, and Del Pozzo G Expression level of risk genes of Major hystocompatibility complex class II is a susceptibility factor for autoimmunity: new insights. Autoimmun. 2018 May;89:1-10. doi: 10.1016/j.jaut.2017.12.016.
7. Strazzullo M* and Matarazzo MR Epigenetic effects of environmental chemicals on reproductive biology, Curr Drug Targets. 2017; * corresponding author
8. Strazzullo M, Gasparrini B, Neglia G, Balestrieri ML, Francioso R, Rossetti C, Nassa G, De Filippo MR, Weisz A, Di Francesco S, Vecchio D, D'Esposito M, D'Occhio MJ, Zicarelli L, Campanile G. Genome-wide transcriptional profiling of buffaloes embryos with normal and retarded development during peri-implantation stage. PLoS One. 2014 Feb 28;9(2):e90027
9. Strazzullo M, Corteggio A, Altamura G, Francioso R, Roperto F, D’Esposito M, Borzacchiello G “Molecular and epigenetic analysis of the Fragile Histidine Triad Tumour suppressor gene in equine sarcoids” BMC Veterinary Research 2012, 8:30.
10. Altamura G*, Strazzullo M*, Corteggio A, Francioso R, Roperto F, D'Esposito M, Borzacchiello G. “O-(6)-methylguanine-DNA methyltransferase in equine sarcoids: molecular and epigenetic analysis”. BMC Vet Res. 2012 Nov 10; 8: 218. *Altamura and Strazzullo contributed equally to the work.
11. Gatto S, Della Ragione F, Cimmino A, Strazzullo M, Fabbri M, Mutarelli M, Ferraro L, Weisz A, D’Esposito M and Matarazzo MR (2010) “Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome”. Epigenetics. 2010 Jul 12; 5(5).
12. Strazzullo M, Rossetti C, Fusco G, Campanile C, Vecchio D, Campanile G, Di Meo GP, Eggen A, Ferrara L, D’Esposito M. (2009) “Genomic characterization and chromosomal mapping of five river buffalo skeletal muscle differentiation master genes” Cytogenet Genome Res. 2010 May 4.
13. Matarazzo MR*, De Bonis ML*, Strazzullo M*, Cerase A, Ferraro, M, Ballestar, E, Esteller, M, Kudo, S, and M. D’Esposito (2007) “Multiple binding of Methyl-CpG and polycomb complexes in long-term gene silencing events” J Cell Physiol 210(3): 711-9 *Matarazzo, De Bonis and Strazzullo contributed equally to the work.
14. Strazzullo M, Cossu A, Baldinu P, Colombino M, Satta MP, Pintus A, Tanda F, De Bonis ML, Cerase A, D'Urso M, D’Esposito M, Palmieri G. (2003) ”High-resolution methylation analysis of HMLH1 promoter in sporadic endometrial and colorectal carcinomas” Cancer, 98 (7): 1540-6
15. Palmieri G*, Strazzullo M* Ascierto PA, Satriano SMR, Daponte A, Castello G, and The Melanoma Group (1999) “PCR-Based detection of circulating melanoma cells as an effective marker of tumor progression”, Journal of Clinical Oncology, 17:304-311. *Palmieri e Strazzullo contributed equally to the work.
16. Huber R, Hansen RS, Strazzullo M, Pengue G, Mazzarella R, Gartler S, D'Urso M, Schlessinger D, Pilia G, D'Esposito M (1999) “DNA Methylation in Transcriptional Repression of Two Differentially Expressed X-linked Genes, GPC3 and SYBL1”. PNAS, 96:616-621.
17. Strazzullo M, Parisi, T, Di Cristofano A, Rocchi M, La Mantia G. (1998) "Characterization and genomic mapping of chimeric ERV9 endogenous retroviruses-host gene transcripts" Gene, 206(1): 77-83
18. Strazzullo M, Majello B, Lania L, La Mantia G. (1994) "Mutational analysis of the human endogenous ERV9 proviruses promoter region", Virology, 200: 686-695.

PROFESSIONAL EXPERIENCE

CNR Researcher at Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, Naples, 2014 – present.

CNR Researcher at Institute for the Animal Production System in the Mediterranean Environment, Naples, 2008 – 2014

CNR Institute for the Animal Production System in the Mediterranean Environment, Naples, Researcher temporary position 2007,

CNR Institute of Genetics and Biophysics, Naples, Fellowship funded by Telethon, 2005

CNR Institute of Genetics and Biophysics, Naples, Researcher temporary position funded by Consorzio Biogem Scarl, 2001 - 2004

National Cancer Institute, Naples, Researcher temporary position funded by Healthy Ministry, 1996 - 2001

Dept. of Genetics, and General and Molecular Biology, University of Study of Naples "Federico II", AIRC fellowship, 1993 - 1995

Dept, of Genetics, and General and Molecular Biology, University of Study of Naples "Federico II", Post−degree Training, 1991-1992.

EDUCATION

Specialist Degree summa cum laude in Medical Genetics, Faculty of Medicine at the University of Rome La Sapienza, Rome, 2000.

Degree summa cum laude in Biology, Faculty of Biological Sciences at the University of Naples Federico II, Naples, 1990