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Andrew Xiao, PhD

Associate Professor of Genetics
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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

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)

Cellular Reprogramming; Chromatin; DNA Damage; Genetics; Histones; Stem Cells

Research at a Glance

Yale Co-Authors

Frequent collaborators of Andrew Xiao's published research.

Publications

2023

2022

2020

2019

2018

Academic Achievements & Community Involvement

  • honor

    Outstanding Early Investigator Awards

  • honor

    Blavatnik Innovation Award

  • honor

    New Scholar Award

  • honor

    NCI Howard Temin Pathway to Independence Award in Cancer Research (K99/R00)

  • honor

    Susan G. Komen for the Cure fellow at Rockefeller University

Get In Touch

Contacts

Academic Office Number
Lab Number

Locations

  • Amistad Street Building

    Academic Office

    10 Amistad Street

    New Haven, CT 06519