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To investigate\n                    <jats:italic>KRT19<\/jats:italic>\n                    expression dynamics, we developed a human pluripotent stem cell (PSC)\u2010based\n                    <jats:italic>KRT19<\/jats:italic>\n                    \u2010\n                    <jats:italic>mCherry<\/jats:italic>\n                    reporter system in different genetic backgrounds to monitor\n                    <jats:italic>KRT19<\/jats:italic>\n                    expression from its endogenous gene locus. A differentiation protocol to generate mature pancreatic duct\u2010like organoids was applied. While\n                    <jats:italic>KRT19<\/jats:italic>\n                    \/\n                    <jats:italic>mCherry<\/jats:italic>\n                    expression became evident at the early endoderm stage, mCherry signal was present in nearly all cells at the pancreatic endoderm (PE) and pancreatic progenitor (PP) stages. Interestingly, despite homogenous KRT19 expression, mCherry positivity dropped to 50% after ductal maturation, indicating a permanent switch from biallelic to monoallelic expression. DNA methylation profiling separated the distinct differentiation intermediates, with site\u2010specific DNA methylation patterns occurring at the\n                    <jats:italic>KRT19<\/jats:italic>\n                    locus during ductal maturation. Accordingly, the monoallelic switch was partially reverted upon treatment with a DNA\u2010methyltransferase inhibitor. In human PDAC cohorts, high\n                    <jats:italic>KRT19<\/jats:italic>\n                    levels correlate with low locus methylation and decreased survival. At the same time, activation of oncogenic KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    signalling in our reporter system reversed monoallelic back to biallelic\n                    <jats:italic>KRT19<\/jats:italic>\n                    expression in pancreatic duct\u2010like organoids. Allelic reactivation was also detected in single\u2010cell transcriptomes of human PDACs, which further revealed a positive correlation between\n                    <jats:italic>KRT19<\/jats:italic>\n                    and\n                    <jats:italic>KRAS<\/jats:italic>\n                    expression. Accordingly,\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutant PDACs had higher\n                    <jats:italic>KRT19<\/jats:italic>\n                    mRNA but lower\n                    <jats:italic>KRT19<\/jats:italic>\n                    gene locus DNA methylation than wildtype counterparts. KRT19 protein was additionally detected in plasma of PDAC patients, with higher concentrations correlating with shorter progression\u2010free survival in gemcitabine\/nabPaclitaxel\u2010treated and opposing trends in FOLFIRINOX\u2010treated patients. Apart from being an important pancreatic ductal lineage marker,\n                    <jats:italic>KRT19<\/jats:italic>\n                    appears tightly controlled via a switch from biallelic to monoallelic expression during ductal lineage entry and is aberrantly expressed after oncogenic KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    expression, indicating a role in PDAC development and malignancy. Soluble KRT19 might serve as a relevant biomarker to stratify treatment. \u00a9 2023 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6156","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T04:46:31Z","timestamp":1691556391000},"page":"139-155","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>DNA<\/scp>\n                    methylation\u2010associated allelic inactivation regulates Keratin 19 gene expression during pancreatic development and carcinogenesis"],"prefix":"10.1002","volume":"261","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0829-2872","authenticated-orcid":false,"given":"Jana","family":"Kr\u00fcger","sequence":"first","affiliation":[{"name":"Institute of Molecular Oncology and Stem Cell Biology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7145-2544","authenticated-orcid":false,"given":"Anja","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Ulm University &amp; Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2817-1974","authenticated-orcid":false,"given":"Markus","family":"Breunig","sequence":"additional","affiliation":[{"name":"Institute of Molecular Oncology and Stem Cell Biology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Allg\u00f6wer","sequence":"additional","affiliation":[{"name":"Institute of Molecular Oncology and Stem Cell Biology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Schulte","sequence":"additional","affiliation":[{"name":"Division of Interdisciplinary Pancreatology, Department of Internal Medicine I Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Merkle","sequence":"additional","affiliation":[{"name":"Organoid Core Facility Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhanie A","family":"Mulaw","sequence":"additional","affiliation":[{"name":"Unit for Single\u2010cell Genomics, Medical Faculty Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nnamdi","family":"Okeke","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Ulm University &amp; Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7902-590X","authenticated-orcid":false,"given":"Michael K","family":"Melzer","sequence":"additional","affiliation":[{"name":"Institute of Molecular Oncology and Stem Cell Biology Ulm University Hospital  Ulm Germany"},{"name":"Department of Urology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7265-7740","authenticated-orcid":false,"given":"Clara","family":"Morgenstern","sequence":"additional","affiliation":[{"name":"Institute of Molecular Oncology and Stem Cell Biology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ninel","family":"Azoitei","sequence":"additional","affiliation":[{"name":"Institute of Molecular Oncology and Stem Cell Biology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas FE","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Pathology Ulm University Hospital  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiner","family":"Siebert","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Ulm University &amp; 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