{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:49:56Z","timestamp":1760233796071,"version":"build-2065373602"},"reference-count":58,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Gestational hypertensive disorders continue to threaten the well-being of pregnant women and their offspring. The only current definitive treatment for gestational hypertensive disorders is delivery of the fetus. The optimal timing of delivery remains controversial. Currently, the available clinical tools do not allow for assessment of fetal stress in its early stages. Placental insufficiency and fetal growth restriction secondary to gestational hypertensive disorders have been shown to have long-term impacts on offspring health even into their adulthood, becoming one of the major focuses of research in the field of developmental origins of health and disease. Fetal reprogramming was introduced to describe the long-lasting effects of the toxic intrauterine environment on the growing fetus. With the advent of high-throughput sequencing, there have been major advances in research attempting to quantify fetal reprogramming. Moreover, genes that are found to be differentially expressed as a result of fetal reprogramming show promise in the development of transcriptional biomarkers for clinical use in detecting fetal response to placental insufficiency. In this review, we will review key pathophysiology in the development of placental insufficiency, existing literature on high-throughput sequencing in the study of fetal reprogramming, and considerations regarding research design from our own experience.<\/jats:p>","DOI":"10.3390\/genes12030329","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T21:16:53Z","timestamp":1614287813000},"page":"329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Quantifying Fetal Reprogramming for Biomarker Development in the Era of High-Throughput Sequencing"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5770-0580","authenticated-orcid":false,"given":"Fu-Sheng","family":"Chou","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krystel","family":"Newton","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Shan","family":"Wang","sequence":"additional","affiliation":[{"name":"PXT Research &amp; Data Analytics, LLC, Rancho Cucamonga, CA 91739, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Michita, R.T., de Lima Kaminski, V., and Chies, J.A.B. (2018). Genetic variants in preeclampsia: Lessons from studies in Latin-American populations. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.01771"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"814543","DOI":"10.1155\/2015\/814543","article-title":"Angiogenesis in the placenta: The role of reactive oxygen species signaling","volume":"2015","author":"Pereira","year":"2015","journal-title":"Biomed Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.ygyno.2017.04.019","article-title":"The immune response in pregnancy and in cancer is active and supportive of placental and tumor cell growth not their destruction","volume":"145","author":"Beaman","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4137\/CMPed.S40070","article-title":"Intrauterine growth restriction: Antenatal and postnatal aspects","volume":"10","author":"Sharma","year":"2016","journal-title":"Clin. Med. Insights Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-physiol-020911-153245","article-title":"Fetal programming and metabolic syndrome","volume":"74","author":"Rinaudo","year":"2012","journal-title":"Annu. Rev. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1097\/MNH.0b013e328326092c","article-title":"Developmental programming and hypertension","volume":"18","author":"Nuyt","year":"2009","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"653","DOI":"10.2174\/156652410792630643","article-title":"Hypoxia and fetal heart development","volume":"10","author":"Patterson","year":"2010","journal-title":"Curr. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Armengaud, J.B., Yzydorczyk, C., Siddeek, B., Peyter, A.C., and Simeoni, U. (2020). Intrauterine growth restriction: Clinical consequences on health and disease at adulthood. Reprod. Toxicol.","DOI":"10.1016\/j.reprotox.2020.10.005"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1001\/archgenpsychiatry.2007.40","article-title":"Depression in young adults with very low birth weight: The Helsinki study of very low-birth-weight adults","volume":"65","author":"Pesonen","year":"2008","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1542\/peds.2014-1143","article-title":"Early childhood neurodevelopment after intrauterine growth restriction: A systematic review","volume":"135","author":"Levine","year":"2015","journal-title":"Pediatrics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"660","DOI":"10.3109\/14767058.2015.1015417","article-title":"Neurodevelopment in children with intrauterine growth restriction: Adverse effects and interventions","volume":"29","author":"Wang","year":"2016","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/S2352-4642(18)30245-1","article-title":"Intrauterine growth restriction and development of the hippocampus: Implications for learning and memory in children and adolescents","volume":"2","author":"Gilchrist","year":"2018","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Korzeniewski, S.J., Allred, E.N., Joseph, R.M., Heeren, T., Kuban, K.C.K., O\u2019Shea, T.M., Leviton, A., and For the ELGAN Study Investigators (2017). Neurodevelopment at age 10 years of children born <28 weeks with fetal growth restriction. Pediatrics, 140.","DOI":"10.1542\/peds.2017-0697"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.brainres.2011.01.032","article-title":"Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: A magnetic resonance imaging study","volume":"1382","author":"Padilla","year":"2011","journal-title":"Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2013.12.007","article-title":"Differential vulnerability of gray matter and white matter to intrauterine growth restriction in preterm infants at 12 months corrected age","volume":"1545","author":"Padilla","year":"2014","journal-title":"Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1113\/JP271402","article-title":"The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome","volume":"594","author":"Miller","year":"2016","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1753-4887.2009.00265.x","article-title":"Fetal programming: Link between early nutrition, DNA methylation, and complex diseases","volume":"68","author":"Chmurzynska","year":"2010","journal-title":"Nutr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1159\/000487618","article-title":"Perinatal origins of adult disease","volume":"113","author":"Simeoni","year":"2018","journal-title":"Neonatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1093\/nutrit\/nux053","article-title":"Developmental origins of health and disease: Current knowledge and potential mechanisms","volume":"75","author":"Hoffman","year":"2017","journal-title":"Nutr. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"T105","DOI":"10.1530\/JOE-19-0009","article-title":"Epigenetic responses and the developmental origins of health and disease","volume":"242","author":"Goyal","year":"2019","journal-title":"J. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3389\/fped.2020.00459","article-title":"The SLC25A42 transcript is a biomarker for fetal reprogramming in response to placental insufficiency in preterm newborns under 32 weeks gestation-a pilot study","volume":"8","author":"Chou","year":"2020","journal-title":"Front. Pediatr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.mrfmmm.2008.01.001","article-title":"Hypoxia induces a novel signature of chromatin modifications and global repression of transcription","volume":"640","author":"Johnson","year":"2008","journal-title":"Mutat. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nrm3327","article-title":"Molecular mechanisms and potential functions of histone demethylases","volume":"13","author":"Kooistra","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1042\/BJ20140754","article-title":"Chromatin and oxygen sensing in the context of JmjC histone demethylases","volume":"462","author":"Shmakova","year":"2014","journal-title":"Biochem J."},{"key":"ref_25","first-page":"89","article-title":"Microarray data analysis for differential expression: A tutorial","volume":"28","author":"Burguete","year":"2009","journal-title":"P R Health Sci. J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Whitehead, C., Teh, W.T., Walker, S.P., Leung, C., Mendis, S., Larmour, L., and Tong, S. (2013). Quantifying circulating hypoxia-induced RNA transcripts in maternal blood to determine in utero fetal hypoxic status. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-256"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e9572","DOI":"10.1097\/MD.0000000000009572","article-title":"Functional analysis of cell-free RNA using mid-trimester amniotic fluid supernatant in pregnancy with the fetal growth restriction","volume":"97","author":"Cho","year":"2018","journal-title":"Medicine"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tarca, A.L., Romero, R., Pique-Regi, R., Pacora, P., Done, B., Kacerovsky, M., Bhatti, G., Jaiman, S., Hassan, S.S., and Hsu, C.-D. (2020). Amniotic fluid cell-free transcriptome: A glimpse into fetal development and placental cellular dynamics during normal pregnancy. BMC Med. Genom., 13.","DOI":"10.1186\/s12920-020-0690-5"},{"key":"ref_29","first-page":"2316","article-title":"Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1","volume":"118","author":"Park","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1177\/1933719109351935","article-title":"Brain renin-angiotensin system: Fetal epigenetic programming by maternal protein restriction during pregnancy","volume":"17","author":"Goyal","year":"2010","journal-title":"Reprod. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1016\/j.ddmod.2013.01.003","article-title":"Intrauterine growth retardation\u2014A developmental model of type 2 diabetes","volume":"10","author":"Pinney","year":"2013","journal-title":"Drug Discov. Today Dis. Models"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s13148-020-00980-9","article-title":"Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction","volume":"12","author":"Terstappen","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.placenta.2019.05.012","article-title":"Disrupted placental serotonin synthetic pathway and increased placental serotonin: Potential implications in the pathogenesis of human fetal growth restriction","volume":"84","author":"Ranzil","year":"2019","journal-title":"Placenta"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hannan, N.J., Stock, O., Spencer, R., Whitehead, C., David, A.L., Groom, K., Petersen, S., Henry, A., Said, J.M., and Seeho, S. (2020). Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth. BMC Med., 18.","DOI":"10.1186\/s12916-020-01605-x"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"202","DOI":"10.2174\/187231211796904955","article-title":"Quantitative analysis of UGT2B28 mRNA expression by real-time RT-PCR and application to human tissue distribution study","volume":"5","author":"Ohno","year":"2011","journal-title":"Drug Metab. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1672-0229(08)60044-3","article-title":"A brief review on the mechanisms of miRNA regulation","volume":"7","author":"Cai","year":"2009","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Awamleh, Z., Gloor, G.B., and Han, V.K.M. (2019). Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia: Potential impact on gene expression and pathophysiology. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0548-x"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.preghy.2020.01.002","article-title":"Identification of miR-210-5p in human placentae from pregnancies complicated by preeclampsia and intrauterine growth restriction, and its potential role in the pregnancy complications","volume":"19","author":"Awamleh","year":"2020","journal-title":"Pregnancy Hypertens."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1007\/s00404-015-3931-7","article-title":"Macrophage colony-stimulating factor (M-CSF) in first trimester maternal serum: Correlation with pathologic pregnancy outcome","volume":"293","author":"Wilke","year":"2016","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1038\/s41467-020-16346-x","article-title":"Circulating SPINT1 is a biomarker of pregnancies with poor placental function and fetal growth restriction","volume":"11","author":"MacDonald","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.bpobgyn.2011.02.004","article-title":"Pre-Eclampsia: Fetal assessment and neonatal outcomes","volume":"25","author":"Gruslin","year":"2011","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"540.e1","DOI":"10.1016\/j.ajog.2011.07.003","article-title":"Neonatal outcome of pregnancies complicated by hypertensive disorders between 34 and 37 weeks of gestation: A 7 year retrospective analysis of a national registry","volume":"205","author":"Langenveld","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sharma, D., Farahbakhsh, N., Shastri, S., and Sharma, P. (2016). Intrauterine growth restriction\u2014Part 2. J. Matern. Fetal Neonatal Med., 1\u201312.","DOI":"10.3109\/14767058.2016.1154525"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fped.2019.00022","article-title":"Sex differences in nutrition, growth, and metabolism in preterm infants","volume":"7","author":"Alur","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_45","first-page":"EC26","article-title":"Changes in haematological parameters in newborns born to preeclamptic mothers\u2014A case control study in a rural hospital","volume":"11","author":"Mouna","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Chen, C.-Y., Essien, M.D., Johnson, A.J., Lee, G.T., and Chou, F.-S. (2019). Use of mean platelet volume in the assessment of intrauterine infection in newborns with combined thrombocytopenia and leukopenia at birth. J. Matern. Fetal Neonatal Med., 1\u20137.","DOI":"10.1080\/14767058.2019.1608174"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kang, J.H., Park, H.J., Jung, Y.W., Shim, S.H., Sung, S.R., Park, J.E., Cha, D.H., and Ahn, E.H. (2015). Comparative transcriptome analysis of cell-free fetal RNA from amniotic fluid and RNA from amniocytes in uncomplicated pregnancies. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132955"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Banerjee, M., and Misra, D. (2012). Fetal nucleic acids in maternal circulation: A genetic resource for noninvasive prenatal diagnosis. ISRN Genet., 2013, Available online: https:\/\/www.hindawi.com\/journals\/isrn\/2013\/961293\/.","DOI":"10.5402\/2013\/961293"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1126\/science.aar3819","article-title":"Noninvasive blood tests for fetal development predict gestational age and preterm delivery","volume":"360","author":"Ngo","year":"2018","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1373\/clinchem.2017.273888","article-title":"Simultaneously monitoring immune response and microbial infections during pregnancy through plasma cfRNA sequencing","volume":"63","author":"Pan","year":"2017","journal-title":"Clin. Chem."},{"key":"ref_51","unstructured":"(2021, February 11). Sequencing Coverage. Available online: https:\/\/www.illumina.com\/science\/technology\/next-generation-sequencing\/plan-experiments\/coverage.html."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s12064-012-0162-3","article-title":"Measurement of mRNA abundance using RNA-seq data: RPKM measure is inconsistent among samples","volume":"131","author":"Wagner","year":"2012","journal-title":"Theory Biosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8527","DOI":"10.3748\/wjg.v21.i28.8527","article-title":"Circulating RNAs as new biomarkers for detecting pancreatic cancer","volume":"21","author":"Kishikawa","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ygyno.2018.10.002","article-title":"RNA sequencing (RNA-Seq) and its application in ovarian cancer","volume":"152","author":"Wang","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"117473","DOI":"10.1016\/j.lfs.2020.117473","article-title":"Circulating microRNAs as biomarkers in cancer diagnosis","volume":"248","author":"Sohel","year":"2020","journal-title":"Life Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12970","DOI":"10.1038\/s41598-019-49498-y","article-title":"NeTFactor, a framework for identifying transcriptional regulators of gene expression-based biomarkers","volume":"9","author":"Ahsen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Fitzgerald, E., Parent, C., Kee, M.Z.L., and Meaney, M.J. (2021). Maternal distress and offspring neurodevelopment: Challenges and opportunities for pre-clinical research models. Front. Hum. Neurosci., 15.","DOI":"10.3389\/fnhum.2021.635304"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/3\/329\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:28:18Z","timestamp":1760160498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/3\/329"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":58,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["genes12030329"],"URL":"https:\/\/doi.org\/10.3390\/genes12030329","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,2,25]]}}}