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Human PGRN is 593aa secreted growth factor, made up of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A\u2013G and paragranulin. While it is thought that PGRN protects against neurodegeneration through its role in inflammation and tissue repair, the role of PGRN and granulins in the nervous system is currently unclear. To better understand this, we prepared recombinant PGRN, granulin A\u2010F and paragranulin, and used these to treat differentiated neuronal SH\u2010SY5Y cells. Using RNA sequencing and bioinformatics techniques we investigated the functional effects of PGRN and the individual granulins upon the transcriptome. For PGRN treatment we show that the main effect of short\u2010duration treatments is the down\u2010regulation of transcripts, supporting that signalling pathway induction appears to be dominant effect. Gene ontology analysis, however, also supports the regulation of biological processes such as the spliceosome and proteasome in response to PGRN treatment, as well as the lysosomal pathway constituents such as CHMP1A, further supporting the role of PGRN in lysosomal function. We also show that the response to granulin treatments involves the regulation of numerous non\u2010coding RNA's, and the granulins cluster into groups of similar activity on the basis of expression profile with paragranulin and PGRN having similar expression profiles, while granulins B, D, E and G appear more similar.<\/jats:p>","DOI":"10.1111\/ejn.13297","type":"journal-article","created":{"date-parts":[[2016,6,16]],"date-time":"2016-06-16T08:32:34Z","timestamp":1466065954000},"page":"2214-2225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis"],"prefix":"10.1111","volume":"44","author":[{"given":"Sara","family":"Rollinson","sequence":"first","affiliation":[{"name":"Institute of Brain Behaviour and Mental Health University of Manchester AV Hill Building, Ackers Street Manchester M13 9PT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Young","sequence":"additional","affiliation":[{"name":"Institute of Brain Behaviour and Mental Health University of Manchester AV Hill Building, Ackers Street Manchester M13 9PT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janis","family":"Bennion\u2010Callister","sequence":"additional","affiliation":[{"name":"Institute of Brain Behaviour and Mental Health University of Manchester AV Hill Building, Ackers Street Manchester M13 9PT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart M.","family":"Pickering\u2010Brown","sequence":"additional","affiliation":[{"name":"Institute of Brain Behaviour and Mental Health University of Manchester AV Hill Building, Ackers Street Manchester M13 9PT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,7,9]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"(2012)Methods tools and pipelines for analysis of Ion PGM\u2122Sequencer miRNA and gene expression data."},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0237313100"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05016"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.200900086"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2007.06.068"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2014.04.009"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20513"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01775-07"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-011-9553-z"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12437"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.25.14863"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn352"},{"key":"e_1_2_7_17_1","first-page":"225","volume-title":"Cell Culture Techniques, Neuromethods","author":"Forsby A.","year":"2011"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2011.04519.x"},{"key":"e_1_2_7_19_1","first-page":"3222","article-title":"Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in\u00a0vivo","volume":"59","author":"He Z.","year":"1999","journal-title":"Cancer Res."},{"key":"e_1_2_7_20_1","first-page":"5590","article-title":"Progranulin (PC\u2010cell\u2010derived growth factor\/acrogranin) regulates invasion and cell survival","volume":"62","author":"He Z.","year":"2002","journal-title":"Cancer Res."},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm816"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05939"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0996-747"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-9-r183"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0812429"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts251"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208857"},{"key":"e_1_2_7_28_1","first-page":"2438","article-title":"Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin","volume":"118","author":"Kessenbrock K.","year":"2008","journal-title":"J. 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