In my research, we study how environmental signals and insults are interpreted by our cells. Our mechanism of focus is epigenetics. Epigenetics refers to the functionally relevant modifications to the genome that do not involve a change in the DNA sequence. Epigenetics is the bridge connecting the environment and genetics, regulating gene expression and cellular response to environmental cues throughout our lifespan. To better understand the role of environmental factors in brain function and dysfunction, we investigate epigenetics, in particular, DNA methylation dynamics during early development and adulthood. We are interested in how physical and/or psychosocial stress can induce epigenetic abnormalities that later lead to neuropathological and psychiatric symptoms. Physical stressors like traumatic brain injury can enhance or contribute to these abnormalities, and psychosocial stressors often precipitate depression and heightened suicide risk. Applying both genomics and computational approaches, we use a combination of animal and human studies to identify genes and genetic pathways that undergo sustained transcriptional regulatory changes in response to such environmental insults.
Chromatin Dynamics in Primate Brain Development
The role of chromatin dynamics in neurodevelopment is widely recognized. Environmental insults during early development pre and peri natally can induce long lasting chromatin modifications resulting in indelible effects on health and disease later in life. Knowledge of the chromatin dynamics of human neurodevelopment is essential for interpretation of epigenetic findings for neurodevelopmental disorders such as autism, schizophrenia, major depression, and anxiety. Our research focuses on delineating DNA methylation and chromatin accessibility dynamics during normal brain development in mammalian genomes. This research has contributed to seminal findings that showed dynamic changes throughout development with non-CG methylation (mCH) accumulating in neurons, but not glia, which then become the dominant form of methylation in the human neuronal genome. Our ongoing research efforts are concerned with characterizing neuronal DNA methylation and chromatin accessibility patterns at single-base resolution within the prefrontal cortex of human and rhesus macaque using state of the art ultra-high throughput sequencing technology. By identifying genomic compartments subject to epigenetic neurodevelopmental regulation, these data provide the framework for interpretation of findings from investigations of neurodevelopmental disorders. This research is foundational for studies of early effects of environment on molecular circuitry of the developing primate brain. How epigenetic mechanisms contribute to the risk for neurodevelopmental and neuropsychiatric disorders is an important focus and a natural progression of our continuing work.
Blast-Related Traumatic Brain Injury
Traumatic brain injury affects 1.7 million Americans each year. Of note, mild TBI is a significant contributor to death and disease in the armed forces and the veteran population returning from wars in Iraq and Afghanistan. It has been estimated that that 10-20% of these returning veterans have suffered a mild TBI and, in many cases, were not diagnosed prior to discharge. Of note, mild TBI is of growing importance to public health with associated comorbid psychopathological symptoms including mood and anxiety disorders, post-traumatic stress disorder, and suicidality. Specifically, research in the lab is focused on identifying transcriptional regulatory changes associated with blast exposure. While blast-related mild TBIs are most well-known in a military setting, they have become increasingly prevalent in the civilian population. Through parallel research tracks involving both rodent and human studies of US Military personnel with exposure to repeated blast in collaboration with the Department of Defense, we have studies underway to identify both acute and chronic transcriptional regulatory changes associated with blast exposure.
Animal model of repeated blast overpressure
To explore the epigenetic changes associated with blast exposure, our projects employ state-of-the-art sequencing and bioinformatics technologies to identify the biochemical changes that influence how genes are expressed in response to blast exposure and associated mild traumatic brain injury (mTBI). Using proven rodent models of blast-related mTBI, we study acute and chronic molecular changes in brain tissue and peripheral blood to shed light on the neurobiological mechanisms underlying mTBI. We profile DNA methylation on a genome-wide scale with techniques like Reduced Representation Bisulfite (RRBS) sequencing to identify transcriptional regulatory regions that are aberrantly methylated following chronic blast exposure. We further investigate the functional significance of these epigenetic changes by performing transcriptional profiling via RNA-seq. This work will aid in discovery of potential gene targets for therapeutic intervention in acute and chronic mTBI.
Human Studies of Effects of Repeated Blast
Translating the findings from our animal studies, we are further interested in determining whether the related molecular epigenetic changes in genes and genetic pathways also detected in human populations. In collaboration with the DoD, we study populations with repeated occupational exposure to low-level blast over multiple exposure events. Profiling DNA methylation and transcriptional changes associated with these exposure events, we are able to characterize the underlying genetic pathways that are influenced by repeated exposure. Because this is a translational study, we are able to link findings using results from both human and clinically relevant animal models as a guide to discover gene targets, thus providing insight into the molecular mechanism of blast-related mTBI.
Neurobiology of Suicide
With the high incidence of suicide amongst individuals with mild TBI, we have developed a complementary research program focusing on neuroinflammatory mechanisms in suicidal behavior. Since suicide is the tenth leading cause of death in the United States and a leading cause of death among US veterans, understanding the etiological basis of suicide risk is critical. Biological markers and environmental risk factors such as TBI and chronic stress likely interact in a complex manner that might benefit from an investigation using genomics approaches that can examine gene by environment interactions. Our research approaches this in a multi-pronged fashion, undertaking clinical, human postmortem, and large-scale data analytic strategies. Our clinical studies involve investigation of genome-scale epigenetics (specifically DNA methylation), transcriptional (RNA-seq), and inflammatory signatures in suicidal veterans.
Through subsequent follow up assessments, we seek to determine how transcriptional regulation is altered following treatment as usual. This observational longitudinal study is a powerful approach to identifying the dynamics of biological markers associated with suicidal behavior. Together, the transcriptional regulatory and inflammatory biological markers of suicide risk will identify objective measures that we can use in clinical settings to identify risk factors of suicide and to determine the efficacy of treatment course and response.
The clinical suicide studies in the lab are also augmented by postmortem human studies. Postmortem studies of suicide victims are vital to our understanding of the neuropathology of suicide. Our lab is focused on delineating the DNA methylation changes that occur in the brains of suicide victims, as compared to non-suicidal individuals in a cell-specific manner. By isolating neuronal and glial cell populations from postmortem brain tissue from both suicidal and non-suicidal individuals, we hope to identify abnormal changes in DNA methylation that are unique to suicide neuropathology. Data generated from this project will accelerate the pace of discovery by introducing an additional layer of information concerning the regulatory circuitry of genes involved in the diathesis of suicide and suicidal behavior.
Further along our postmortem line of research, we investigate whether the blood-brain barrier (BBB) may be compromised in suicidal behavior. Relatively static changes in systemic or CNS immunity, possibly related to psychiatric diseases, injury, or chronic stressors (e.g. combat, abuse) could compromise the BBB. Increased cross-talk between peripheral and central immune system in a feed-forward cycle could culminate in behavioral changes that include suicide. Such processes can be detected by noninvasive brain imaging and blood biomarkers of suicide. Using isolated microvessels from suicide victims and non-psychiatric controls, we assess the blood-brain barrier at the molecular level using genome-scale epigenetics, transcriptomics, and proteomics assays. Once the role of BBB in suicide is stablished through this Omics study, BBB impairment can be detected by routine radiological procedures or by levels of CNS proteins (e.g., S100B in serum, microglial activation can be detected by PET scan, cytokines can be measured in blood or cerebrospinal fluid). Ideally, combinations of these tests could identify who is at risk for suicide and when, allowing for timely intervention. Ultimately, risk of suicide may be reduced by interventions affecting BBB and neuroinflammation.
In our most recent avenue of suicide risk exploration, our lab was selected to join the analytic effort of the Million Veteran Program consortium to study genetic factors and suicidal subtypes using data collected on approximately 600,000 veterans to date. The availability of such big data will allow us to develop machine learning algorithms for identification of suicidal subtypes and biological risk factors associated with suicidal behavior. Taken together, this multi-faceted research strategy offers an integrated approach to gain insight into the clinical features and molecular mechanisms of suicidal behavior.
Neurobiology of Sleep Disturbances in TBI and Suicide
Sleep disturbances are common following traumatic brain injury, and occur particularly frequently in veterans who have sustained traumatic brain injury. In epidemiological studies of military members with blast-related TBI, sleep disturbances can mediate subsequent development of PTSD and depression, both of which can increase suicidal risk. Because TBI, PTSD, and depression have overlapping symptoms, especially symptoms associated with sleep problems, it is difficult to know whether the presence of one condition is a precursor to another. Given the preponderance of sleep disturbances following TBI, this may be an early indicator of development of subsequent psychiatric disorders and heightened risk for suicidal behavior. In our lab, we are developing a rodent model of blast and sleep by performing electroencephalographic sleep recordings on rodents with repeated blast exposure. This will allow us to determine changes in sleep architecture associated with blast. Furthermore, we are determining DNA methylation and transcriptional changes in brain regions key in sleep circuitry. The data generated by this project will further our understanding of sleep changes accompanying mild TBI and the associated molecular mechanisms.
Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression.
Milekic M, Xin Y, O’Donnell A, Kumar K, Bradley-Moore M, Malaspina D, Paul S, Moore H, Ge Y, Edwards J, Haghighi F, and Gingrich J. (2014). Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression. Molecular Psychiatry [Epub ahead of print]. PMID: 25092244
Haghighi F, Xin Y, Chanrion B, O’Donnell AH, Ge Y, Dwork AJ, Arango V, and Mann JJ. (2014). Increased DNA Methylation in the Suicide Brain. Dialogues Clin Neurosci, 16(3):430-8. PMID: 25364291
Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, and Ecker JR. (2013). Global epigenomic reconfiguration during mammalian brain development. Science, 341(6146), 1237905. PMID: 23828890
Deo AJ, Huang YY, Hodgkinson CA, Xin Y, Oquendo MA, Dwork AJ, Arango V, Brent DA, Goldman D, Mann JJ, and Haghighi F. (2013). A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction. Psychiatr Genet, 23(2), 47-55. PMID: 23277131
Xin Y, O’Donnell AH, Ge Y, Chanrion B, Milekic M, Rosoklija G, Stankov A, Arango V, Dwork AJ, Mann JJ, Gingrich J, Haghighi F. (2011). Role of CpG Context and Content in Evolutionary Signatures of Brain DNA Methylation. Epigenetics, 6(11), 1308-18. PMID: 22048252
Xin Y, Ge Y, Haghighi FG. (2011). Methyl-Analyzer—whole genome DNA methylation profiling. Journal of Bioinformatics, 27(16), 2296-7. PMID:21685051
Xin Y, Chanrion B, Liu M, Galfalvy H, Costa R, Ilievski B, Rosoklija G, Arango V, Dwork A, Mann JJ, TyckoB, Haghighi F. Genome-Wide Divergence of DNA Methylation Marks in Cerebral and Cerebellar Cortices. PLoS One. 5(6), e11357. PMID: 20596539
Meet the Team
InBae (Brian) Choi
Biological Research Technician
Associate Researcher II
Adjunct Assistant Professor
Clinical Research Coordinator
Adjunct Assistant Professor
Job opportunities are available in the Laboratory of Medical Epigenetics. Internationally regarded for its dedication to medical science, Mount Sinai is home to an array of leading research institutes, centers, and laboratories, all of which work toward rapidly translating advances in basic science into innovative patient care. Mount Sinai’s Fishberg Department of Neuroscience, a major component of Mount Sinai’s Friedman Brain Institute, sponsors innovative research in basic and translational neuroscience at the molecular, cellular, systems, and behavioral levels. The Haghighi laboratory is studying the epigenetic profiles of human brain development and its emerging role in gene regulation, as well as its fundamental importance for our understanding of normal and pathological neuronal function. Epigenetic patterns in the genome vary among tissues and cell types in normal and pathological states.
A major unanswered question is how epigenetics plays a role in neuronal development and how alterations in normal epigenetic processes during development lead to neurodevelopmental diseases such as autism and schizophrenia. Next-gen sequencing technologies now allow a global view of whole genome epigenetic profiles. Studies involve statistical and bioinformatic analyses of data from whole genome DNA and histone methylation profiling via BS-seq and ChIP-seq to detect differentially methylated regions associated with disease and their potential function through genomic data mining. This interdisciplinary group offers an excellent environment to uncover new fundamental principles and regulatory mechanisms in this emerging area of neural epigenetics.