Ateneo - UPO

Macro subjects proposed during the course are related to molecular evolution of eukaryotic genomes (phylogenesis and phylogenetic trees; human mutation rate; evolution of eukaryotic gene order); regulation of gene expression in eukaryotes (main regulatory mechanisms and induction of cellular types; diseases related to regulatory mechanisms; dynamics of genome accessibility; identification and functions of regulatory sequences; function and features of regulatory sequences; enhancer function; transcriptional factors functions; mechanisms driving transcriptional stress responses and development); epigenetics (epigenetic chromatin modifications; DNA methylation patterns in plants and animals); genome editing; cancer genetics (onco-suppressor and oncogenes; molecular bases of tumours; quantitative and multiplexed functional cancer genomics; heterogeneity in cancer; principles of epigenetic therapy; mechanisms of cancer resistance in long- lived mammals); nutrigenomics (polymorphisms and nutrition; nutraceutics and gene expression; genetics of food intolerances and of detoxification).

Genetica, Binelli e Ghisotti, EdiSes, ed. 2018 Genetica, Pierce, Zanichelli, ed. 2016 Korf e Irons, Genetica e genomica umane, edi-ermes, ed. 2015 Principi di genetica, Snustad D.P., Simmons M.J., EdiSes, ed. 2014 Nutrigenomica ed epigenetica: dalla biologia alla clinica, EDRA ed. 2017 Nature Reviews Genetics 2012, 13: 745-753 Nature Review Genetics 2004, 5: 299-310 Nature Reviews Genetics 2011, 12:554-564 Nature Reviews Genetics 2014, 15:453-468 Nature Reviews Genetics 2011, 12:283-293 Nature Reviews Genetics 2018, 19:385-397 Nature Reviews Genetics 2010, 11:204-220 Nature Reviews Genetics 2014, 15:93-106 Nature Reviews Genetics 2018, 19:741-755 Nature Reviews Genetics 2019, 20:404-41 Nature Reviews Genetics 2019, 19:151-161 Nature Reviews Cancer 2018, 18:433-441 Other publications referred to specific topics have been reported on the slides which have been made available to students.

Teaching purpose is to deepen several concepts of genomics and nutrigenomics. Selected topics are characterized for being subjects (or for potentially having) of practical applications in several sectors of human and plant genetics. During the course, detailed information are provided about genes and genetics processes, as well as indications about the transfer to application sectors of knowledge derived from the genomics topics (genomes evolution, gene expression regulation, epigenetics, genome editing, cancer genomics, nutrigenomics). Information about active web sites have been provided for several of the lessons topics, from which additional information can be derived and/or making possible data analysis with those already present in the web site databases. Therefore, the student is provided with a up to date and deep background about important sectors of genomics and nutrigenomics, to allow her/him to deal with different genetics-related problem, that she/he could meet during his biologist profession, in a critical and proactive behaviour.

Knowledge of qualitative and quantitative genetics, genetic analysis, molecular genetics, biotechnology, will favour understanding of the course topics

Teaching procedure: traditional with PowerPoint slides. The course is organized in 48 hours of frontal lessons. Frontal lessons will be carried out by projection of PowerPoint slides. Teaching materials of the course, as well as a pdf copy of the scientific reviews used during the course, will be made available through the UPO DIR platform.

Course organization involves the utilization of several scientific reviews, where overlapping topics are frequently present. Lessons are informal and interactive, so that students can enquire about lesson topics during every step of the lesson. At the end of each lesson, students are allowed to ask for additional explanations about eventually poorly understood topics. Students with physical disabilities, Learning Disabilities or Special Education Needs can request specific services and tools via the Staff Sviluppo e Coordinamento Carriere e Servizi alle Studentesse e agli Studenti, consulting the University webpage: https://www.uniupo.it/en/services/services-students-physical-or-learning- disabilities Students with disabilities, learning disabilities or special education needs, once they have contacted the University Staff, can refer to the tutor in charge of the course to define the examination modalities, concerning academic aspects.

Examination procedure: written test. Lessons attendance is strongly suggested. Examination intends to evaluate skills of the student in applying concepts learned during the course. Examination is a written test that will include questions with multiple answers. Questions will cover all the topics of the course, available time is 2 hours. The written test include 31 questions; if students respond correctly to all the questions the achieved score is 30 and praise (maximum and excellence score); for each wrong answer or not provided, one point is subtracted, until the score of 18 (minimum score). Possible additional information about examination procedures will be described at the beginning of the course.

• 1 Genomes molecular evolution. Phylogenetic trees; procedures to build phylogenetic trees (UPGMA, NJ, MP, ML metods). Revising the human mutation rate: approaches to estimate genome mutation rates; evolution of the estimation parameters of evolution rate and revision of evolutionary divergences in humans. Evolutionary dynamics of Eukaryotic gene order: non-random organization of gene order; mechanisms governing co- expression and linkage in Eukaryotic genes. • 2 Regulation of Eukaryotic gene expression. Main mechanisms of gene expression regulation. Transcriptional programs and pluripotent/differentiated cells. Mutations in regulatory regions and pathological phenotypes. Mutations in splicing and related pathology. Dynamics of genome accessibility: procedure used to assess accessibility to genomic regions; factors affecting nucleosome occupancy; variations in chromatin structure. Regulatory sequences: approaches for their identification; relationships among predicted and in vivo regulatory binding sites; how binding sites structure affect transcription. Enhancer: effects of epigenetic modifications on enhancer functions; chromosome conformation capture and effects of tridimensional conformations on enhancer functions. How transcription factors work: mechanisms of direct and indirect mechanisms of transcription factor cooperativity; enhancers activity models; enhancers dynamic changes during progression of cellular development; synergic and hierarchical cooperation in enhancer function. Molecular mechanisms of stress transcriptional response: transcriptional reprogramming in stress response; activation and repression of genes in esponse to stress. • 3 Epigenetics. Main epigenetic modifications in DNA and histones. Writers and readers. Non-coding RNAs. DNA methylation patterns in plant and animals: de novo methylation in mammals and plants (epigenetic processes in the germinal lineages); maintaining CG methylation patterns in animals and plants and CHG in plants; active and passive DNA demethylation. RNA-mediated epigenetic regulation of gene expression: small-RNA guided DNA methylation in plants and yeast. Epigenetic regulation of cellular differentiation: epigenetic landscape of embryonic stem (ES) cells and differentiation-related modifications; chromatin modifications during embryo pre-implantation development; chromatin pre-patterning for lineage specification; stability of chromatin modifications. • 4 Genome editing. Available editing systems (ZFNs, TALENs, CRISPR/CAS9, Prime editing); DSB repairing pathways in DNA editing; details about how CRISPR/CAS9 works and its origin; examples of CRISPR/CAS9 applications in plants; evolution and additional applications of CRISPR/CAS9 in genomic analyses. • 5 Cancer genetics. Cancer and cell cycle; examples of tumours originated from chromosomal rearrangements; onco-suppressors and their main functions; retroviruses and viral oncogenes; proto-oncogenes; oncogenes activating mechanisms; some indications on oncogenesis molecular bases. Cancer functional genomics, quantitative and multiplexed approaches: complexity of cancer genetic alterations; in vivo functional evaluation of tumour suppressors, oncogenes and fusion genes; multiplexed functional analyses. Heterogeneity in cancer: genetic evolution in tumours: positive, negative, punctuated evolution, bulk- and single-cell sequencing, sampling; approaches to verify selection in tumours; cancer pattern evolution and implications; evolution of resistance to treatments. Epigenetic approaches in cancer: effects of DNA methylation inhibitors (DNMTi) in epigenetic therapies; effects of DNMTi on ERVs reactivation; epigenetic therapy response pathways; CTL epigenetic reprogramming. Mechanisms of cancer resistance in longlived mammals. • 6 Nutrigenomics: polymorphisms and nutrition (transporters and membrane receptors, transduction systems, enzymes and proteins effectors and structural proteins); nutraceutics and gene expression (epigenetic effects and regulation of gene expression of several molecules with nutraceutical effect); food intolerance genetics (lactose intolerance; intolerance and sensitivity to gluten; histamine intolerance); detoxification and detoxification system. Gender mainstreaming: approaches to grant equal benefits in actions and activities for women and mens and for eliminating gender inequalities.

Knowledge and understanding: it is expected that with a Genomics and nutrigenomics course, characterized by several specific and characterizing topics, the obtained specific knowledge level will be in agreement with International standards. This will allow the student to deal with genetic problems in the human/animal, plant and nutrition sectors.