James Noonan, PhD
Research & Publications
Our current research program is focused on deciphering the role of gene regulatory changes in the evolution of uniquely human traits, particularly the expansion and elaboration of the human cerebral cortex. Our initial efforts targeted a class of elements that we and others first characterized over a decade ago: Human Accelerated Regions (HARs). These elements are highly conserved across species but show many human-specific changes, suggesting they encode uniquely human functions of potentially large effect. We have since expanded the scope of our work to globally identify human-specific regulatory innovations using experimental methods. Our current research is aimed at understanding the phenotypes these regulatory changes specify using humanized mouse models, massively parallel genetic screens, and cellular models of primate neurodevelopment.
Specialized Terms: Human Evolution; Evolutionary Dynamics of Gene Regulation; Synthetic Biology; Applications of Ultra-High Throughput Sequencing Technologies; Comparative and Functional Genomics in Vertebrates
Extensive Research Description
Our laboratory has made multiple contributions over the last decade. We were the first to discover that HARs encode transcriptional enhancers with human-specific activity in the developing embryo (Prabhakar et al. 2008). We have since pioneered the development of humanized mouse models to understand how HARs alter developmental gene expression and drive the evolution of novel phenotypes. In a recent study, we found that the HAR HACNS1 upregulates expression of the transcription factor gene Gbx2 in limb bud chondrogenic mesenchyme, suggesting the human-specific gain of function in HACNS1 contributed to changes in skeletal patterning in human limb evolution (Dutrow et al. 2019).
We also developed methods to map and quantify the activity of gene regulatory elements during mammalian organogenesis, and to identify their gene targets (Cotney et al. 2012 and DeMare et al. 2013). Building on this work, we implemented comparative epigenetics approaches to identify uniquely human regulatory innovations by direct analysis of developing human and nonhuman tissues. This work discovered thousands of promoters and enhancers that have gained activity during human limb and neocortical development (Cotney et al. 2013 and Reilly et al. 2015). These studies have also identified biological pathways in limb and cortical development potentially altered by human-specific regulatory changes, providing the basis for understanding their effects using genetic and experimental models. We also leveraged these findings to understand general principles of developmental enhancer evolution and identify specific regulatory innovations contributing to the emergence of the mammalian neocortex (Emera et al. 2016). We also demonstrated that a major autism risk gene, CHD8, directly regulates other autism-associated genes during neurodevelopment, providing an entry point for deciphering gene regulatory networks contributing to autism risk (Cotney et al. 2015).
In the last several years, we have adopted massively parallel screening approaches to characterize gene regulatory functions contributing to the development and evolution of the human brain. We used massively parallel genome editing in human neural stem cells to disrupt thousands of enhancers active during human cortical development and identify enhancers, including HARs, required for neural stem cell self renewal (Geller et al. 2019). This study established a clear biological function for HARs in neurodevelopment. We have also used massively parallel reporter assays in neural stem cells to measure the effect of >32,000 uniquely human sequence changes on enhancer activity (Uebbing and Gockley et al. 2021).
Embryonic and Fetal Development; Genetics; Evolution, Molecular; Genomics; Gene Regulatory Networks; Epigenomics; Neurodevelopmental Disorders
- A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertensionGunawardhana K, Hong L, Rugira T, Uebbing S, Kucharczak J, Mehta S, Karunamuni D, Cabera-Mendoza B, Gandotra N, Scharfe C, Polimanti R, Noonan J, Mani A. A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension Journal Of Clinical Investigation 2023, 133: e160036. PMID: 36602864, PMCID: PMC9927944, DOI: 10.1172/jci160036.
- Modeling uniquely human gene regulatory function via targeted humanization of the mouse genomeDutrow EV, Emera D, Yim K, Uebbing S, Kocher AA, Krenzer M, Nottoli T, Burkhardt DB, Krishnaswamy S, Louvi A, Noonan JP. Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome Nature Communications 2022, 13: 304. PMID: 35027568, PMCID: PMC8758698, DOI: 10.1038/s41467-021-27899-w.
- Massively parallel discovery of human-specific substitutions that alter enhancer activityUebbing S, Gockley J, Reilly SK, Kocher AA, Geller E, Gandotra N, Scharfe C, Cotney J, Noonan JP. Massively parallel discovery of human-specific substitutions that alter enhancer activity Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 118: e2007049118. PMID: 33372131, PMCID: PMC7812811, DOI: 10.1073/pnas.2007049118.
- 36SINGLE CELL RNA SEQUENCING OF EMBRYONIC MOUSE CORTEX REVEALS OVERLAPPING AND DISTINCT PATTERNS OF ASD RISK GENE EXPRESSIONMuhle R, Yim K, Krenzer M, Hill-Teran G, Malison K, Noonan J. 36SINGLE CELL RNA SEQUENCING OF EMBRYONIC MOUSE CORTEX REVEALS OVERLAPPING AND DISTINCT PATTERNS OF ASD RISK GENE EXPRESSION European Neuropsychopharmacology 2019, 29: s1087. DOI: 10.1016/j.euroneuro.2018.08.043.
- Abstract 5306: SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embeddingAmodio M, Srinivasan K, Dijk D, Mohsen H, Yim K, Muhle R, Moon K, Montgomery R, Noonan J, Wolf G, Krishnaswamy S. Abstract 5306: SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding Cancer Research 2018, 78: 5306-5306. DOI: 10.1158/1538-7445.am2018-5306.
- 5.8 Mapping Regulatory Networks of Autism Risk at Cellular Resolution during NeurodevelopmentMuhle R, Niu W, Hill-Teran G, Yim K, Krenzer M, Abdallah S, Krishnaswamy S, Noonan J. 5.8 Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment Journal Of The American Academy Of Child & Adolescent Psychiatry 2017, 56: s255. DOI: 10.1016/j.jaac.2017.09.291.
- Origin and evolution of developmental enhancers in the mammalian neocortexEmera D, Yin J, Reilly SK, Gockley J, Noonan JP. Origin and evolution of developmental enhancers in the mammalian neocortex Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e2617-e2626. PMID: 27114548, PMCID: PMC4868431, DOI: 10.1073/pnas.1603718113.
- Chromatin Immunoprecipitation with Fixed Animal Tissues and Preparation for High-Throughput SequencingCotney J, Noonan J. Chromatin Immunoprecipitation with Fixed Animal Tissues and Preparation for High-Throughput Sequencing Cold Spring Harbor Protocols 2015, 2015: pdb.err087585. PMID: 25834253, PMCID: PMC5956515, DOI: 10.1101/pdb.err087585.
- The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopmentCotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment Nature Communications 2015, 6: 6404. PMID: 25752243, PMCID: PMC4355952, DOI: 10.1038/ncomms7404.
- Evolutionary changes in promoter and enhancer activity during human corticogenesisReilly SK, Yin J, Ayoub AE, Emera D, Leng J, Cotney J, Sarro R, Rakic P, Noonan JP. Evolutionary changes in promoter and enhancer activity during human corticogenesis Science 2015, 347: 1155-1159. PMID: 25745175, PMCID: PMC4426903, DOI: 10.1126/science.1260943.
- Evolution of Gene Regulation in HumansReilly S, Noonan J. Evolution of Gene Regulation in Humans Annual Review Of Genomics And Human Genetics 2014, 17: 1-23. DOI: 10.1146/annurev-genom-090314-045935.
- The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic LimbCotney J, Leng J, Yin J, Reilly SK, DeMare LE, Emera D, Ayoub AE, Rakic P, Noonan JP. The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb Cell 2013, 154: 185-196. PMID: 23827682, PMCID: PMC3785101, DOI: 10.1016/j.cell.2013.05.056.
- The genomic landscape of cohesin-associated chromatin interactionsDeMare LE, Leng J, Cotney J, Reilly SK, Yin J, Sarro R, Noonan JP. The genomic landscape of cohesin-associated chromatin interactions Genome Research 2013, 23: 1224-1234. PMID: 23704192, PMCID: PMC3730097, DOI: 10.1101/gr.156570.113.
- Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limbCotney J, Leng J, Oh S, DeMare LE, Reilly SK, Gerstein MB, Noonan JP. Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb Genome Research 2012, 22: 1069-1080. PMID: 22421546, PMCID: PMC3371702, DOI: 10.1101/gr.129817.111.
- Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencingAyoub AE, Oh S, Xie Y, Leng J, Cotney J, Dominguez MH, Noonan JP, Rakic P. Transcriptional programs in transient embryonic zones of the cerebral cortex defined by high-resolution mRNA sequencing Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 14950-14955. PMID: 21873192, PMCID: PMC3169109, DOI: 10.1073/pnas.1112213108.
- Genomics of Long-Range Regulatory ElementsNoonan JP, McCallion AS. Genomics of Long-Range Regulatory Elements Annual Review Of Genomics And Human Genetics 2010, 11: 1-23. PMID: 20438361, DOI: 10.1146/annurev-genom-082509-141651.
- Corrigendum to “Gene regulation and the origins of human biological uniqueness.” [Trends in Genetics, 26/3 (2010) 110–118]Sholtis S, Noonan J. Corrigendum to “Gene regulation and the origins of human biological uniqueness.” [Trends in Genetics, 26/3 (2010) 110–118] Trends In Genetics 2010, 26: 344. DOI: 10.1016/j.tig.2010.05.002.
- Response to Comment on "Human-Specific Gain of Function in a Developmental Enhancer"Prabhakar S, Visel A, Akiyama J, Shoukry M, Lewis K, Holt A, Plajzer-Frick I, Morrison H, FitzPatrick D, Afzal V, Pennacchio L, Rubin E, Noonan J. Response to Comment on "Human-Specific Gain of Function in a Developmental Enhancer" Science 2009, 323: 714-714. DOI: 10.1126/science.1166571.
- Human-Specific Gain of Function in a Developmental EnhancerPrabhakar S, Visel A, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Morrison H, FitzPatrick DR, Afzal V, Pennacchio LA, Rubin EM, Noonan JP. Human-Specific Gain of Function in a Developmental Enhancer Science 2008, 321: 1346-1350. PMID: 18772437, PMCID: PMC2658639, DOI: 10.1126/science.1159974.
- Accelerated Evolution of Conserved Noncoding Sequences in HumansPrabhakar S, Noonan JP, Pääbo S, Rubin EM. Accelerated Evolution of Conserved Noncoding Sequences in Humans Science 2006, 314: 786-786. PMID: 17082449, DOI: 10.1126/science.1130738.