Andrew Xiao, PhD
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Associate Professor of Genetics
Biography
Dr. Andrew Xiao is an associate professor in the Department of Genetics at the Yale University School of Medicine. He is a member of the Yale Stem Cell Center. Dr. Xiao’s laboratory focuses on epigenetic regulation in pluripotent stem cells, including embryonic stem cells and induced pluripotenct stem cells (iPSC). His laboratory has made significant contributions to the understanding of the maintenance of pluripotency, as well as the recent discovery of novel epigenetic mechanisms, i.e., N6-methyl-adenine, in mammalian genomes. Dr. Xiao received his Ph.D degree from Terry Van Dyke’s lab at UNC-Chapel Hill and postdoctoral training from David Allis’ lab at Rockefeller University. Since 2009, Andrew Xiao is a recipient of the NCI Howard Temin Award in Cancer Research (K99/R00) and in 2012, he received the New Scholar Award from the Ellison Medical Foundation. He is a recipient of the Outstanding Early Investigator Awards from the Ludwig Family Foundation since 2015.
Appointments
Genetics
Associate Professor TenurePrimary
Other Departments & Organizations
Education & Training
- Postdoctoral Fellow
- The Rockefeller University (2009)
- PhD
- University of North Carolina at Chapel Hill (2003)
- BS
- Peking University Medical Center (1994)
Research
Overview
The essential components of epigenetics- The basic unit of our genome is nucleosomes, a complex in which ~146 bases of the DNA molecule wrap around a group of proteins called histones.Histones are among the most conserved proteins during evolution; only a few differences in their composition (amino acid residues) are found among yeast and human histones.
Intriguingly, higher eukaryotic genomes, especially the mammalian, contain specialized histones, known as the histone variants, which are often only presented in a very small portion of the genome (1-5%) and yet play critical roles in various biological process, ranging from differentiation/development to DNA repair/replication. A major research interest in my lab is to understand how the deposition and functions of histone variants are regulated.A recent work from my lab discovered unexpected roles of a histone variant in determination of the quality of cell induced pluripotent stem (iPS) cells (Wu et al. 2014).
Chemical modifications on histones is a very important aspect of epigenetic regulation; more than a hundred such modifications have been discovered to date. On the other hand, the dogma stated that 5-methyl-Cytidine (5mC) and its derivatives is the only form of chemical modification on mammalian DNA.Other modifications, such as N6-methyl-adenine (N6-mA) had been long thought to only exist in bacteria, viruses and a limited number of simple eukaryotes. Our most recent discovery of N6-mA “puts paid to” this dogma (Nature news and view). This paradigm-shifting discovery opens up a brand new research direction in mammalian epigenetics, which we are excited to explore (Wu et al. 2016).
DNA secondary structures induced by superhelical tension during replication and transcription is a long-standing observation. Our recent discovery of a novel role of N6-mA in regulating DNA secondary structures (Li et al., 2020) open a new research direction. We have elucidated the molecular pathways of this regulation and revealed its function in early embryogenesis.
Last but not least, we are interested in endogenous retrotransposons in mammalian genomes.These remnants of the ancient viruses once invaded our genome and later became domesticated. Although long considered as “junk” DNA, they have received lots of attention recently as they play surprising roles in ES cells and early embryogenesis.First, they are considered as a driving force in genome evolution; as Barbara McClintock pointed out several decades ago, they are the key factor for an organism to develop new traits under environmental stress. Second, recent studies have implicated them in early development, especially at morula stage embryos (2-cell to 16-cell). Third, their frequent (50%) remobilization (de novo jumping) in human carcinomas (breast, prostate, colon etc) has been implicated in tumor progression. Therefore, we are striving to understand the epigenetic mechanisms for regulating retrotransposon functions.
Our interests in stem cells and cellular reprogramming- Embryonic stem cells, which can self-renew endlessly and differentiate into every cell type in the human body, contain the blueprints of our existence. They hold the promise of curing any disease or condition caused by tissue loss or aging, including Alzheimer’s, Huntington’s and blood cell loss from chemotherapy.Due to ethical concerns, however, the availability of embryonic stem cells is highly limited. In addition, given the diversity of human populations, transplanting cells derived from a few common lines of embryonic stem cells may lead to immune rejection and other complications in a patient population.The recent advent of cellular reprogramming technology, a breakthrough that was recognized with the Noble Prize in 2012, provides an attractive solution to these issues.With the addition of a few genes, differentiated cells (such as skin or hair follicle cells) can be “reprogrammed” to become like embryonic stem cells and then further induced into cells of interest. This means that if cellular reprogramming becomes medically viable, a patient with Alzheimer’s disease can be cured by cells derived from her own skin or hair, which would be free from the risk of immune rejection. Although promising, current cellular reprogramming technology needs significant improvements for future clinical applications to become feasible. A major gateway issue is the uneven quality among reprogrammed cell lines: over 95% of reprogrammed cells do not behave like embryonic stem cells.Therefore, understanding the mechanisms controlling the quality of reprogrammed cells and ultimately developing novel methods to improve their quality is not only a fundamental question for those of us engaged in basic scientific research, but of great importance to regenerative medicine.Our laboratory has recently shed the first light on this intriguing “quality control” issue by demonstrating the surprising role of histone variant in determination of the cell fate stability of iPS cells.
Moreover, since the epigenetic landscape of stem cells are drastically different from that of differentiated cells, we also use stem cells as a valuable source in search of novel epigenetic mechanism. One good example is the discovery of N6-mA. Although rare in normal adult tissues and cells, these mechanisms are often “hijacked” by human diseases, so these mechanisms serve as perfect therapeutic targets.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Raman Nelakanti
Mei Zhong, PhD
Myles Alderman III, PhD
Akiko Iwasaki, PhD
Giulia Biancon, PhD
Huabing Li, PhD
Histones
DNA Damage
Cellular Reprogramming
Chromatin
Stem Cells
Publications
2022
Taming the transposon: H3K9me3 turns foe to friend in human development
Chitrakar A, Noon M, Xiao AZ. Taming the transposon: H3K9me3 turns foe to friend in human development. Cell Stem Cell 2022, 29: 1009-1010. PMID: 35803220, PMCID: PMC9484580, DOI: 10.1016/j.stem.2022.06.010.Peer-Reviewed Original ResearchCitationsMeSH Keywords
2020
A New Link to Primate Heart Development
Nelakanti RV, Xiao AZ. A New Link to Primate Heart Development. Developmental Cell 2020, 54: 685-686. PMID: 32991832, DOI: 10.1016/j.devcel.2020.09.009.Commentaries, Editorials and LettersCitationsAltmetricMeSH Keywords and ConceptsN6-methyladenine in DNA antagonizes SATB1 in early development
Li Z, Zhao S, Nelakanti RV, Lin K, Wu TP, Alderman MH, Guo C, Wang P, Zhang M, Min W, Jiang Z, Wang Y, Li H, Xiao AZ. N6-methyladenine in DNA antagonizes SATB1 in early development. Nature 2020, 583: 625-630. PMID: 32669713, PMCID: PMC8596487, DOI: 10.1038/s41586-020-2500-9.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsN6-mAN6-methyladenineMouse trophoblast stem cellsLarge chromatin domainsCell fate transitionsLarge-scale chromatinUnexpected molecular mechanismTrophoblast stem cellsEarly embryonic developmentDNA secondary structuresEarly developmentFate transitionsMammalian genomesChromatin domainsEpigenetic landscapeGene regulationChromatin organizerEmbryonic developmentDNA modificationsBiological roleMolecular mechanismsSATB1 functionsMolecular pathwaysCell culture modelSecondary structurem6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
Gao Y, Vasic R, Song Y, Teng R, Liu C, Gbyli R, Biancon G, Nelakanti R, Lobben K, Kudo E, Liu W, Ardasheva A, Fu X, Wang X, Joshi P, Lee V, Dura B, Viero G, Iwasaki A, Fan R, Xiao A, Flavell RA, Li HB, Tebaldi T, Halene S. m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development. Immunity 2020, 52: 1007-1021.e8. PMID: 32497523, PMCID: PMC7408742, DOI: 10.1016/j.immuni.2020.05.003.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsDouble-stranded RNADeleterious innate immune responseMammalian hematopoietic developmentEndogenous double-stranded RNAHematopoietic developmentInnate immune responseAbundant RNA modificationMurine fetal liverPattern recognition receptor pathwaysImmune responseProtein codingDsRNA formationRNA modificationsWriter METTL3Hematopoietic defectsPerinatal lethalityNative stateConditional deletionAberrant innate immune responsesLoss of METTL3Hematopoietic failureReceptor pathwayAberrant immune responsePrevents formationFetal liverRNA-based CRISPR-Mediated Loss-of-Function Mutagenesis in Human Pluripotent Stem Cells
Leung AW, Broton C, Bogacheva MS, Xiao AZ, Garcia-Castro MI, Lou YR. RNA-based CRISPR-Mediated Loss-of-Function Mutagenesis in Human Pluripotent Stem Cells. Journal Of Molecular Biology 2020, 432: 3956-3964. PMID: 32339532, DOI: 10.1016/j.jmb.2020.04.017.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsHuman pluripotent stem cellsPluripotent stem cellsTargeting efficiencyShelf cell productsTransfection protocolShort palindromic repeatsStem cellsSelection markerGenome editingPS cell linesFunction mutagenesisImproved protocolBroad applicationsPalindromic repeatsClustered RegularlyAssociated 9Human therapyEfficiencyProtocolCell productsCRISPRCrRNARegularlyApplicationsEditingMammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA
Zhang M, Yang S, Nelakanti R, Zhao W, Liu G, Li Z, Liu X, Wu T, Xiao A, Li H. Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA. Cell Research 2020, 30: 197-210. PMID: 32051560, PMCID: PMC7054317, DOI: 10.1038/s41422-019-0237-5.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsN6-mAMammalian genomesStructure-based mutagenesis studiesBase unpairing regionsChromosome regulationDNA demethylasesStructural studiesEpigenetic marksDNA demethylaseMouse genomeEarly embryogenesisGenomic studiesBase flippingN6-methyladenineALKBH1Mutagenesis studiesFlipped baseGenomeProfiling studiesDNACatalytic centerDemethylaseActive regulationRegulationDemethylases
2019
N(6)-Methyladenine in eukaryotes
Alderman MH, Xiao AZ. N(6)-Methyladenine in eukaryotes. Cellular And Molecular Life Sciences 2019, 76: 2957-2966. PMID: 31143960, PMCID: PMC6857450, DOI: 10.1007/s00018-019-03146-w.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and Concepts
2018
N 6 -methyladenine DNA Modification in Glioblastoma
Xie Q, Wu TP, Gimple RC, Li Z, Prager BC, Wu Q, Yu Y, Wang P, Wang Y, Gorkin DU, Zhang C, Dowiak AV, Lin K, Zeng C, Sui Y, Kim LJY, Miller TE, Jiang L, Lee-Poturalski C, Huang Z, Fang X, Zhai K, Mack SC, Sander M, Bao S, Kerstetter-Fogle AE, Sloan AE, Xiao AZ, Rich JN. N 6 -methyladenine DNA Modification in Glioblastoma. Cell 2018, 175: 1228-1243.e20. PMID: 30392959, PMCID: PMC6433469, DOI: 10.1016/j.cell.2018.10.006.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAdenineAdultAgedAlkB Homolog 1, Histone H2a DioxygenaseAnimalsAstrocytesBrain NeoplasmsCell HypoxiaChildDNA MethylationEpigenomicsFemaleGlioblastomaHeterochromatinHistonesHumansKaplan-Meier EstimateMaleMiceMiddle AgedNeoplastic Stem CellsRNA InterferenceRNA, Small InterferingTumor Suppressor Protein p53ConceptsDNA modificationsHeterochromatic histone modificationsRegulation of transcriptionNovel DNA modificationChromatin accessibilityEpigenetic marksHistone modificationsTranscriptional silencingEpigenetic modificationsGenetic driversHuman diseasesOncogenic pathwaysTumor cell proliferationPotential therapeutic targetALKBH1Cell proliferationTumor-bearing miceCritical roleTherapeutic targetDNAHuman tissuesHuman glioblastoma modelGlioblastoma modelGlioblastomaSilencingMapping and characterizing N6-methyladenine in eukaryotic genomes using single-molecule real-time sequencing
Zhu S, Beaulaurier J, Deikus G, Wu TP, Strahl M, Hao Z, Luo G, Gregory JA, Chess A, He C, Xiao A, Sebra R, Schadt EE, Fang G. Mapping and characterizing N6-methyladenine in eukaryotic genomes using single-molecule real-time sequencing. Genome Research 2018, 28: 1067-1078. PMID: 29764913, PMCID: PMC6028124, DOI: 10.1101/gr.231068.117.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSingle-molecule real-time sequencingEukaryotic genomesReal-time sequencingDAS eventsN6-methyladenineHuman lymphoblastoid cellsGenome-wide mapsSingle-nucleotide resolutionSingle-molecule resolutionLINE-1 elementsFull-length LINE-1 elementsGreen algaeProkaryotic genomesGenomeHigh-resolution mappingSequencing dataLymphoblastoid cellsSequencingEukaryotesProkaryotesMethylomeNovel formAlgaePromoterJoint analysis
2017
Quality control towards the application of induced pluripotent stem cells
Lin K, Xiao AZ. Quality control towards the application of induced pluripotent stem cells. Current Opinion In Genetics & Development 2017, 46: 164-169. PMID: 28823985, DOI: 10.1016/j.gde.2017.07.006.Peer-Reviewed Original ResearchCitationsAltmetric
Academic Achievements and Community Involvement
honor Outstanding Early Investigator Awards
Yale University AwardLudwig Family FoundationDetails07/04/2018United Stateshonor Blavatnik Innovation Award
Yale University AwardDetails06/02/2017United Stateshonor New Scholar Award
National AwardEllison Medical FoundationDetails08/01/2012United Stateshonor NCI Howard Temin Pathway to Independence Award in Cancer Research (K99/R00)
National AwardNIH/NCIDetails01/01/2009United Stateshonor Susan G. Komen for the Cure fellow at Rockefeller University
National AwardSusan G. Komen for the CureDetails01/01/2006United States
Links & Media
News
- February 28, 2024
Grants Awarded at YCC • 2024
- August 03, 2023
Lung Adenocarcinomas: New Findings About Resistance to Targeted Therapies
- June 23, 2023
Dr. Raman Nelakanti Awarded the 2023 Slayman Prize in Genetics
- July 15, 2020Source: YaleNews
Simple Twist of DNA Determines Fate of Placenta
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