Integrative Biology

Team

Bonnal Raoul JP, Staff Scientist bonnal@ingm.org
Curti Serena, Laboratory Technician curti@ingm.org
Dardanelli Alessia, PhD Student dardanelli@ingm.org
De Simone Marco, Post Doc desimone@ingm.org
Della Chiara Giulia, Post Doc dellachiara@ingm.org
Fakiola Michaela, Senior Post Doc fakiola@ingm.org
Godano Chiara, Student godano@ingm.org
Gruarin Paola, Researcher gruarin@ingm.org
Panzeri Ilaria, Post Doc panzeri@ingm.org
Politano Claudia, PhD Student politano@ingm.org
Ranzani Valeria, Post Doc ranzani@ingm.org
Rossetti Grazisa, Staff Scientist rossetti@ingm.org
Sarnicola Maria Lucia, Technician sarnicola@ingm.org
Vangelisti Silvia, Student vangelisti@ingm.org

Scientific Background

Integrative Biology is a multidisciplinary research approach that emphasizes the amalgamation of expertise from different sub-disciplines. Integrative Biology Program is devoted to deciphering the molecular mechanisms and the regulatory networks underlying T cell differentiation and plasticity in the human immune system. We will be employing several techniques and multiple know-how in fields like, molecular and cellular biology, biochemistry, genomics, transcriptomics and bioinformatics.

Key Publications

De novo transcriptome profiling of highly purified human lymphocytes primary cells.
Bonnal RJ, Ranzani V, Arrigoni A, Curti S, Panzeri I, Gruarin P, Abrignani S, Rossetti G, Pagani M.
Sci Data. 2015 Sep 29;2:150051.

The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4
Ranzani V, Rossetti G, Panzeri I, Arrigoni A, Bonnal RJP, Curti S, Gruarin P, Provasi E, Sugliano E, Marconi M, De Francesco R, Geginat J, Bodega B, Abrignani S, Pagani M.
Nature Immunol. 2015 Jan 26. DOI:10.1038/ni.3093

Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation
Pagani M, Rossetti G, Panzeri I, de Candia P, Bonnal RJ, Rossi RL, Geginat J, Abrignani S.
Immunol Rev. 253(1):82-96, 2013.

Distinct microRNA signatures in human lymphocyte subsets and enforcement of T cell naïve state by miR-125b
Rossi RL., Rossetti G., Wenandy L., Curti S., Ripamonti A., Bonnal RJP., Sciarretta BR., Moro M., Crosti MC., Gruarin P., Maglie S., Marabita F., Mascheroni D., Parente V., Comelli M., Trabucchi E., De Francesco R., Geginat J., Abrignani S., Pagani M.
Nature Immunol. 12, 796-803, 2011.

Ongoing Projects

  1. Identification of Micrornas Involved in Differentiation Of Human T Lymphocytes
    In recent years it has become clear that microRNAs play a pivotal role in regulation of gene expression. MicroRNAs are small non-coding RNAs ~22 nucleotides long that bind mostly to the 3′ UTR of target mRNAs, thereby affecting transcript stability and/or translation. Several human microRNAs identified so far show tissue or development stage-specific expression profiles, suggesting that they are integrated in the regulatory networks defining cellular identity. Our group firstly focused on the identification of those microRNAs defining the different human T-lymphocytes subsets. Integration of these data with gene expression profiling allowed us to identify microRNA specifically involved in lymphocyte differentiation, in particular of CD4+ T cells subsets. The functional relevance on CD4+ T cell differentiation of some of the identified microRNAs is being further investigated. Aberrant expression of microRNAs has been implicated in numerous disease states, and microRNA-based diagnostics and/or therapy will be investigated in certain diseases.
  2. Studies on Epigenetic Regulation of Human Lymphocytes by Long non-Coding RNAs.
    Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNA (tRNA) or ribosomal RNA (rRNA), as well as microRNAs, siRNA and the class of long non-coding RNAs which plays a key role in gene regulation, genome stability and chromatin modification. Long non-codingRNAs epigenetically regulate several physio-pathological processes, including development, cell differentiation, cancer, inflammation and chronic viral infection. Thus, regulation of long non-codingRNAs has the potential of being an important mechanism in preserving and altering lymphocyte cell phenotypes. Thus, we need to deeply understand, when and how expression of key long non-codingRNAs changes during T cell differentiation and how they can influence epigenetic regulation. To address these questions, we are performing a whole transcriptome analysis of highly purified human lymphocyte subsets by deep-sequencing, in order to identify the differentially expressed long non-codingRNAs in human lymphocyte subsets. Long non-codingRNAs emerging from our combined experimental and bioinformatics analysis will be further investigated to define their precise functional role(s) through gain and loss of function experiments.
  3. Long non-coding RNAs of tumor infiltrating lymphocytes as novel anti-cancer therapeutic targets.
    Although tumor tissues can be infiltrated by T cells specific for tumor antigens, the effector functions of these lymphocytes are generally suppressed by CD4+ regulatory T cells (Tregs). However, tumor infiltrating Tregs can display function heterogeneity, depending on both the tumor type and the inflammatory milieu. Thus, only inhibition of the right Treg activity should result in the unleash of an effective anti-tumor T cell responses. With the aim of identifying the Tregs that truly inhibit anti-tumor T cells, here we will profile by RNA-Seq the transcriptome of Tregs infiltrating both tumor and healthy tissues. In particular, we will focus on lncRNAs and the gene networks they modulate, since they have recently emerged as relevant epigenetic regulators of cell differentiation and identity. We will exploit this new knowledge to determine the association of specific transcripts with different Treg cell populations, including those specific for truly inhibitory Tregs. Since downregulation of specific lncRNAs might be an efficient way to inhibit the “unwanted” Tregs at tumor sites, we aim at targeting lncRNAs uniquely expressed in these Tregs and propose to develop AsiCs, chimeric molecules composed by an aptamer, single stranded oligonucleotides that bind to cell surface markers, and a siRNA, short RNAs downregulating specific lncRNAs.

Recent Publications

The light and the dark sides of Interleukin-10 in immune-mediated diseases and cancer
Geginat J, Larghi P, Paroni M, Nizzoli G, Penatti A, Pagani M, Gagliani N, Meroni P, Abrignani S, Flavell RA.
Cytokine Growth Factor Rev. 2016 Mar 8. pii: S1359-6101(16)30019-3. doi: 10.1016/j.cytogfr.2016.02.003. [Epub ahead of print]

The circulating microRNome demonstrates distinct lymphocyte subset-dependent signatures
de Candia P, Torri A, Fedeli M, Viganò V, Carpi D, Gorletta T, Casorati G, Pagani M, Dellabona P and Abrignani S
Eur J Immunol. (2015) Dec 7. doi: 10.1002/eji.201545787. [Epub ahead of print]

De novo transcriptome profiling of highly purified human lymphocytes primary cells
Bonnal RJP, Ranzani V, Arrigoni A, Curti S, Panzeri I, Gruarin P, Abrignani S, Rossetti G, Pagani M.
Scientific Data (2015) 2, Article number: 150051 (2015) doi:10.1038/sdata.2015.51

Hepatitis C Virus Deletion Mutants Are Found in individuals Chronically Infected with Genotype 1 Hepatitis C Virus in Association with Age, High Viral Load and Liver Inflammatory Activity
Cheroni C, Donnici L, Aghemo A, Balistreri F, Bianco A, Zanoni V, Pagani M, Soffredini R, D’Ambrosio R, Rumi MG,Colombo M, Abrignani S, Neddermann P, De Francesco R.
PLoS One. (2015) Sep 25;10(9):e0138546.

Signal strength and metabolic requirements control Th17 differentiation of uncommitted human T cells
Kastirr I, Crosti MC, Maglie S, Paroni M, Steckel B, Moro M, Pagani M, Abrignani S, Geginat J.
J Immunol. (2015) Oct 15;195(8):3617-27.

Reference proteome of highly purified human Th1 cells reveals strong effects on metabolism and protein ubiquitination upon differentiation
Pagani M, Rockstroh M, Schuster M, Rossetti G, Moro M, Crosti M and Tomm JM.
PROTEOMICS (2015), DOI: 10.1002/pmic.201400139

IL-10 producing Foxp3- regulatory T-cells inhibit B-cell responses and are involved in systemic lupus erythematosus
Facciotti F, Gagliani N, Häringer B, Alfen JS, Penatti A, Maglie S, Paroni M, Iseppon A, Moro M, Crosti MC, Stölzel K, Romagnani C, Moroni G, Ingegnoli F, Torretta S, Pignataro L, Annoni A, Russo P, Pagani M, Abrignani S, Meroni PL, Flavell RA and. Geginat J
J Allergy Clin Immunol. (2015) Aug 25. pii: S0091-6749(15)00999-9. doi: 10.1016/j.jaci.2015.06.044.

Defects During Mecp2 Null Embryonic Cortex Development Precede the Onset of Overt Neurological Symptoms
Bedogni F, Cobolli Gigli C, Pozzi D, Rossi RL, Scaramuzza L, Rossetti G, Pagani M, Kilstrup-Nielsen C, Matteoli M, Landsberger N.
Cerebral Cortex (2015), doi: 10.1093/cercor/bhv078

miRiadne: a web tool for consistent integration of miRNA nomenclature
Bonnal RJP, Rossi RL, Carpi D, Ranzani V, Abrignani S, Pagani M.
Nucleic Acids Res. (2015) Jul 1;43(W1):W487-92.

The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4.
Ranzani V, Rossetti G, Panzeri I, Arrigoni A, Bonnal RJP, Curti S, Gruarin P, Provasi E, Sugliano E, Marconi M, De Francesco R, Geginat J, Bodega B, Abrignani S, Pagani M.
Nature Immunol. 2015 Jan 26. DOI:10.1038/ni.3093

Serum microRNAs as Biomarkers of Human Lymphocyte Activation in Health and Disease.
de Candia P, Torri A, Pagani M, Abrignani S.
Frontiers in Immunology. 2014 Feb 10;5:43. eCollection 2014. Review.

The CD4-centered universe of human T cell subsets
Geginat J, Paroni M, Facciotti F, Gruarin P, Kastirr I, Caprioli F, Pagani M, Abrignani S.
Seminars in Immunology. 2013 Nov 15;25(4):252-62.

Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation
de Candia P, Torri A, Gorletta T, Fedeli M, Bulgheroni E, Cheroni C, Marabita F, Crosti M, Moro M, Pariani E, Romanò L, Esposito S, Mosca F, Rossetti G, Rossi RL, Geginat J, Casorati G, Dellabona P, Pagani M, Abrignani S.
PLoS One. 2013 Sep 26;8(9):e75348.

Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation
Pagani M, Rossetti G, Panzeri I, de Candia P, Bonnal RJ, Rossi RL, Geginat J, Abrignani S.
Immunol Rev. 2013 May;253(1):82-96.

Reduction of CD68+ Macrophages and Decreased IL-17 Expression in Intestinal Mucosa of Patients with Inflammatory Bowel Disease Strongly Correlate With Endoscopic Response and Mucosal Healing following Infliximab Therapy.
Caprioli F, Bosè F, Rossi RL, Petti L, Viganò C, Ciafardini C, Raeli L, Basilisco G, Ferrero S, Pagani M, Conte D, Altomare G, Monteleone G, Abrignani S, Reali E.
Inflammatory Bowel Diseases. 2013; 19 (4): 729-739

Identification of new autoantigens by protein array indicates a role for IL4 neutralization in Autoimmune Hepatitis.
Zingaretti C, Arigò M, Cardaci A, Moro M, Crosti M, Sinisi A, Sugliano E, Cheroni C, Marabita F, Nogarotto R, Bonnal R, Marcatili P, Marconi M, Zignego A, Muratori P, Invernizzi P, Colombatto P, Brunetto M, Bonino B, De Francesco R, Geginat J, Pagani M, Muratori L, Abrignani S, Bombaci M .
Molecular and Cellular Proteomics. 2012; 11 (12), pp. 1885-1897

Identification of new hematopoietic cell subsets with a polyclonal antibody library specific for neglected proteins.
Moro M, Crosti M, Creo P, Gallina P, Curti S, Sugliano E, Scavelli R, Cattaneo D, Canidio E, Marconi M, Rebulla P, Sarmientos P, Viale G, Pagani M, Abrignani S.
PLoS ONE. 2012; 7 (4), art. no. e34395

Biogem: an effective tool-based approach for scaling up open source software development in bioinformatics.
Bonnal RJ, Aerts J, Githinji G, Goto N, Maclean D, Miller CA, Mishima H, Pagani M, Ramirez-Gonzalez R, Smant G, Strozzi F, Syme R, Vos R, Wennblom TJ, Woodcroft BJ, Katayama T, Prins P.
Bioinformatics. 2012; 28 (7), art. no. bts080 , pp. 1035-1037

Circulating Hepatitis B Surface Antigen Particles Carry Hepatocellular microRNAs.
Novellino L, Rossi RL, Bonino F, Cavallone D, Abrignani S, Pagani M, Brunetto MR.
PLoS ONE. 2012; 7 (3), art. no. e31952

Metabolism of Phosphatidylinositol 4-Kinase IIIα-Dependent PI4P Is Subverted by HCV and Is Targeted by a 4-Anilino Quinazoline with Antiviral Activity.
Bianco A, Reghellin V, Donnici L, Fenu S, Alvarez R, Baruffa C, Peri F, Pagani M, Abrignani S, Neddermann P, De Francesco R.
PLoS Pathogens. 2012; 8 (3), art. no. e1002576

A novel polyclonal antibody library for expression profiling of poorly characterized membrane and secreted human proteins.
Grifantini R, Pagani M, Pierleoni A, Grandi A, Parri M, Campagnoli S, Pileri P, Cattaneo D, Canidio E, Pontillo A, De Camilli E, Bresciani A, Marinoni F, Pedrazzoli E, Nogarotto R, Abrignani S, Viale G, Sarmientos P, Grandi G.
Journal of Proteomics. 2011; 75 (2), pp. 532-547

Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b
Rossi RL, Rossetti G, Wenandy L, Curti S, Ripamonti A, Bonnal RJP, Sciarretta BR, Moro M, Crosti MC, Gruarin P, Maglie S, Marabita F, Mascheroni D, Parente V, Comelli M, Trabucchi E, De Francesco R, Geginat J, Abrignani S, Pagani M.
Nature Immunology. 2011; 12 (8), pp. 796-803

Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output.
Celona B, Weiner A, Di Felice F, Mancuso FM, Cesarini E, Rossi RL, Gregory L, Baban D, Rossetti G, Grianti P, Pagani M, Bonaldi T, Ragoussis J, Friedman N, Camilloni G, Bianchi ME, Agresti A.
PLoS Biology. 2011; 9 (6), art. no. e1001086

A high-resolution anatomical atlas of the transcriptome in the mouse embryo.
Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nurnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, Grabbe F, Sieverding C, Fischer B, Schrader K, Brockmeyer M, Dettmer S, Helbig C, Alunni V, Battaini MA, Mura C, Henrichsen CN, Garcia-Lopez R, Echevarria D, Puelles E, Garcia-Calero E, Kruse S, Uhr M, Kauck C, Feng G, Milyaev N, Ong CK, Kumar L, Lam M, Semple CA, Gyenesei A, Mundlos S, Radelof U, Lehrach H, Sarmientos P, Reymond A, Davidson DR, Dolle P, Antonarakis SE, Yaspo ML, Martinez S, Baldock RA, Eichele G, Ballabio A.
PLoS Biology. 2011; 9 (1), art. no. e1000582

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