{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T17:47:24Z","timestamp":1774806444199,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,9]]},"group-title":"Genetics","reference-count":114,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIA","award":["K99AG068271"],"award-info":[{"award-number":["K99AG068271"]}]},{"name":"NIA","award":["R00AG068271"],"award-info":[{"award-number":["R00AG068271"]}]},{"name":"NIA","award":["R01AG085357"],"award-info":[{"award-number":["R01AG085357"]}]},{"name":"HudsonAlpha Foundation","award":["Memory and Mobility Program"],"award-info":[{"award-number":["Memory and Mobility Program"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer\u2019s Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA.\n                  <jats:italic>MAPT<\/jats:italic>\n                  codes for Tau, therefore understanding how the\n                  <jats:italic>MAPT<\/jats:italic>\n                  gene is regulated and the effect of genetic variation at its regulatory elements is likely to have high relevance for tauopathies. We screened a \u223c3 Mb region including the\n                  <jats:italic>MAPT<\/jats:italic>\n                  locus using 2 different massively parallel reporter assay (MPRA) strategies in KOLF2.1J h-NGN2 neurons and HEK293FT cells, identifying previously unannotated cis-regulatory elements (CREs). Using CRISPR interference (CRISPRi) in mixed neuron cultures, we identified a new CRE for\n                  <jats:italic>MAPT<\/jats:italic>\n                  , as well as 2 CREs for another nearby gene of interest,\n                  <jats:italic>KANSL1<\/jats:italic>\n                  . Known genetic variation from the Alzheimer\u2019s Disease sequencing project was tested in a separate MPRA at the top CREs near the\n                  <jats:italic>MAPT<\/jats:italic>\n                  gene, identifying variants with altered regulatory effects including those at previously identified CREs for\n                  <jats:italic>MAPT<\/jats:italic>\n                  . Using a saturation mutagenesis screen of a 2,000 bp region encompassing the\n                  <jats:italic>MAPT<\/jats:italic>\n                  promoter, we assessed regulatory effects of each possible single nucleotide variant in this region. We identified several neuron-specific regulatory variant effects at this region, including a high confidence binding site for the transcription factors EGR2, ZBTB14, and TCLF5 at a region of high MPRA activity and genetic conservation.\n                <\/jats:p>","DOI":"10.64898\/2026.03.06.710116","type":"posted-content","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T23:56:41Z","timestamp":1773273401000},"source":"Crossref","is-referenced-by-count":0,"title":["Promoter mutagenesis and a massively parallel reporter screen of the\n                  <i>MAPT<\/i>\n                  locus identifies cis-regulatory elements and genetic variation effects"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8771-3895","authenticated-orcid":false,"given":"Rebecca M.","family":"Hauser","sequence":"first","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry L.","family":"Limbo","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Nicholas","family":"Brazell","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4381-7540","authenticated-orcid":false,"given":"Belle A.","family":"Moyers","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0751-9697","authenticated-orcid":false,"given":"Shelby N.","family":"Lauzon","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin A.","family":"Barinaga","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Quinn","family":"Johnston","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3708-4805","authenticated-orcid":false,"given":"Brianne B.","family":"Rogers","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared W.","family":"Taylor","sequence":"additional","affiliation":[{"name":"HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA 35806"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9852-5504","authenticated-orcid":false,"given":"J. 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