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Kai-Lieh Huang, Ph.D.

Kai-Lieh Huang, Ph.D.

Contact

Office (585) 276-3425

About Me

Faculty Appointments

Research Assistant Professor - Department of Biochemistry and Biophysics (SMD)

Credentials

Post-doctoral Training & Residency

University of Texas Medical Branch | Galveston, Texas | Mentor: Dr. Eric Wagner 2017 - 2021

Education

PhD | University of Texas Health Science Center - Houston. Biochemistry and Molecular Biology. 2016

M.Sc. | National Sun Yat-sen University. Molecular Biology. 2003

B.Sc. | National Sun Yat-sen University. Biological Sciences. 2001

Research

My research focuses on understanding how RNA polymerase II (RNAPII) transcription is regulated, with a particular emphasis on promoter-proximal pausing and transcription termination. Over the past five years, my work has centered on defining the molecular functions of the Integrator complex as a glo...
My research focuses on understanding how RNA polymerase II (RNAPII) transcription is regulated, with a particular emphasis on promoter-proximal pausing and transcription termination. Over the past five years, my work has centered on defining the molecular functions of the Integrator complex as a global regulator of RNAPII. Through a combination of genomic, biochemical, and genetic approaches, I have helped establish Integrator as a central coordinator of RNAPII promoter-proximal pause release.

Promoter-proximal pausing represents a critical checkpoint in transcription, at which RNAPII must either transition into productive elongation or be terminated. While pausing has long been appreciated as a regulatory step, the mechanisms enforcing termination at paused polymerases—and the consequences of failure at this checkpoint—were largely unknown. Using a rapid protein depletion system (auxin-degron) and genome-wide nascent transcription profiling (RNA-seq, TT-seq, and PRO-seq), we demonstrated that Integrator’s catalytic endonuclease subunit, INTS11, is responsible for promoter-proximal termination across essentially the entire RNAPII transcriptome. Loss of Integrator-mediated cleavage leads to widespread failure of early termination, resulting in increased RNAPII escape from promoters but inefficient productive elongation, particularly at long genes.

We further uncovered how Integrator integrates two enzymatic activities to control transcriptional outcomes. In addition to its RNA endonuclease activity mediated by INTS11, Integrator recruits Protein Phosphatase 2A (PP2A) to paused RNAPII complexes. This interaction, mediated by specific Integrator subunits including INTS8, counteracts kinase-driven pause release by dephosphorylating the RNAPII C-terminal domain and the elongation factor SPT5. By antagonizing P-TEFb–dependent phosphorylation, Integrator-associated PP2A stabilizes the paused state and creates a permissive window for RNA cleavage and termination. Together, these studies highlight Integrator as a multifunctional regulatory hub at early transcriptional checkpoints.

More recently, my research has expanded to explore the downstream consequences of defective Integrator function. We found that loss of Integrator does not simply alter transcriptional output, but fundamentally compromises RNA quality control. In the absence of proper promoter-proximal termination, aberrant transcripts enriched for retained introns and repetitive elements accumulate. These RNAs form double-stranded RNA structures that are recognized by innate immune sensors, leading to activation of PKR and the integrated stress response (ISR). This work uncovered a direct mechanistic link between transcription termination defects and cellular stress signaling, demonstrating that Integrator suppresses endogenous dsRNA formation and prevents inappropriate activation of antiviral-like pathways. Importantly, these effects are observed not only in experimental systems but also in cells harboring disease-associated Integrator mutations, suggesting that chronic ISR activation may contribute to Integrator-related human pathologies.

Looking forward, my research aims to further define how Integrator activity is modulated across cellular states and how its dysfunction contributes to disease. Key open questions include how Integrator distinguishes productive from nonproductive transcription complexes, how termination outcomes intersect with RNA processing and nuclear surveillance pathways, and whether stress-response signaling downstream of transcriptional defects can be therapeutically targeted. By continuing to integrate mechanistic biochemistry with genome-scale approaches, my goal is to understand how early transcriptional decisions shape cellular homeostasis.

Publications

Journal Articles

Integrator loss leads to dsRNA formation that triggers the integrated stress response.

Baluapuri A, Zhao NC, Marina RJ, Huang KL, Kuzkina A, Amodeo ME, Stein CB, Ahn LY, Farr JS, Schaffer AE, Khurana V, Wagner EJ, Adelman K

Cell.. 2025 June 12188 (12):3184-3201.e21. Epub 04/14/2025.

The TRIM-NHL RNA-binding protein Brain Tumor coordinately regulates expression of the glycolytic pathway and vacuolar ATPase complex.

Connacher RP, Roden RT, Huang KL, Korte AJ, Yeruva S, Dittbenner N, DesMarais AJ, Weidmann CA, Randall TA, Williams J, Hall TMT, Wagner EJ, Goldstrohm AC

Nucleic acids research.. 2024 November 1152 (20):12669-12688. Epub 1900 01 01.

Cytoplasmic binding partners of the Integrator endonuclease INTS11 and its paralog CPSF73 are required for their nuclear function.

Lin MH, Jensen MK, Elrod ND, Chu HF, Haseley M, Beam AC, Huang KL, Chiang W, Russell WK, Williams K, Pröschel C, Wagner EJ, Tong L

Molecular cell.. 2024 August 884 (15):2900-2917.e10. Epub 07/19/2024.

A UL26-PIAS1 complex antagonizes anti-viral gene expression during Human Cytomegalovirus infection.

Ciesla J, Huang KL, Wagner EJ, Munger J

PLoS pathogens.. 2024 May 20 (5):e1012058. Epub 05/20/2024.

NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1.

Jonnakuti VS, Ji P, Gao Y, Lin A, Chu Y, Elrod N, Huang KL, Li W, Yalamanchili HK, Wagner EJ

Journal of neuro-oncology.. 2023 July 163 (3):623-634. Epub 06/30/2023.

Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.

de Prisco N, Ford C, Elrod ND, Lee W, Tang LC, Huang KL, Lin A, Ji P, Jonnakuti VS, Boyle L, Cabaj M, Botta S, Õunap K, Reinson K, Wojcik MH, Rosenfeld JA, Bi W, Tveten K, Prescott T, Gerstner T, Schroeder A, Fong CT, George-Abraham JK, Buchanan CA, Hanson-Khan A, Bernstein JA, Nella AA, Chung WK, Brandt V, Jovanovic M, Targoff KL, Yalamanchili HK, Wagner EJ, Gennarino VA

Science advances.. 2023 February 179 (7):eade4814. Epub 02/17/2023.

Integrator endonuclease drives promoter-proximal termination at all RNA polymerase II-transcribed loci.

Stein CB, Field AR, Mimoso CA, Zhao C, Huang KL, Wagner EJ, Adelman K

Molecular cell.. 2022 November 1782 (22):4232-4245.e11. Epub 10/28/2022.

INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.

Mascibroda LG, Shboul M, Elrod ND, Colleaux L, Hamamy H, Huang KL, Peart N, Singh MK, Lee H, Merriman B, Jodoin JN, Sitaram P, Lee LA, Fathalla R, Al-Rawashdeh B, Ababneh O, El-Khateeb M, Escande-Beillard N, Nelson SF, Wu Y, Tong L, Kenney LJ, Roy S, Russell WK, Amiel J, Reversade B, Wagner EJ

Nature communications.. 2022 October 1313 (1):6054. Epub 10/13/2022.

Inositol hexakisphosphate is required for Integrator function.

Lin MH, Jensen MK, Elrod ND, Huang KL, Welle KA, Wagner EJ, Tong L

Nature communications.. 2022 September 3013 (1):5742. Epub 09/30/2022.

An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability.

Li L, Huang KL, Gao Y, Cui Y, Wang G, Elrod ND, Li Y, Chen YE, Ji P, Peng F, Russell WK, Wagner EJ, Li W

Nature genetics.. 2021 July 53 (7):994-1005. Epub 05/13/2021.

Integrator Recruits Protein Phosphatase 2A to Prevent Pause Release and Facilitate Transcription Termination.

Huang KL, Jee D, Stein CB, Elrod ND, Henriques T, Mascibroda LG, Baillat D, Russell WK, Adelman K, Wagner EJ

Molecular cell.. 2020 October 1580 (2):345-358.e9. Epub 09/22/2020.

Tob2 phosphorylation regulates global mRNA turnover to reshape transcriptome and impact cell proliferation.

Chen CA, Strouz K, Huang KL, Shyu AB

RNA.. 2020 September 26 (9):1143-1159. Epub 05/13/2020.

The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes.

Elrod ND, Henriques T, Huang KL, Tatomer DC, Wilusz JE, Wagner EJ, Adelman K

Molecular cell.. 2019 December 576 (5):738-752.e7. Epub 1900 01 01.

The Integrator complex cleaves nascent mRNAs to attenuate transcription.

Tatomer DC, Elrod ND, Liang D, Xiao MS, Jiang JZ, Jonathan M, Huang KL, Wagner EJ, Cherry S, Wilusz JE

Genes & development.. 2019 November 133 (21-22):1525-1538. Epub 09/17/2019.

Integrator subunit 4 is a 'Symplekin-like' scaffold that associates with INTS9/11 to form the Integrator cleavage module.

Albrecht TR, Shevtsov SP, Wu Y, Mascibroda LG, Peart NJ, Huang KL, Sawyer IA, Tong L, Dundr M, Wagner EJ

Nucleic acids research.. 2018 May 446 (8):4241-4255. Epub 1900 01 01.

Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor.

Kivlin CM, Watson KL, Al Sannaa GA, Belousov R, Ingram DR, Huang KL, May CD, Bolshakov S, Landers SM, Kalam AA, Slopis JM, McCutcheon IE, Pollock RE, Lev D, Lazar AJ, Torres KE

Cancer biology & therapy.. 2016 17 (2):129-38. Epub 12/09/2015.

Phosphorylation at intrinsically disordered regions of PAM2 motif-containing proteins modulates their interactions with PABPC1 and influences mRNA fate.

Huang KL, Chadee AB, Chen CY, Zhang Y, Shyu AB

RNA.. 2013 March 19 (3):295-305. Epub 01/22/2013.

Dual targeting of mTOR and aurora-A kinase for the treatment of uterine Leiomyosarcoma.

Brewer Savannah KJ, Demicco EG, Lusby K, Ghadimi MP, Belousov R, Young E, Zhang Y, Huang KL, Lazar AJ, Hunt KK, Pollock RE, Creighton CJ, Anderson ML, Lev D

Clinical cancer research : an official journal of the American Association for Cancer Research.. 2012 September 118 (17):4633-45. Epub 07/20/2012.

Expression of 'drugable' tyrosine kinase receptors in malignant peripheral nerve sheath tumour: potential molecular therapeutic targets for a chemoresistant cancer.

Torres KE, Liu J, Young E, Huang KL, Ghadimi M, Lusby K, Lazar AJ, Lev D

Histopathology.. 2011 July 59 (1):156-9. Epub 1900 01 01.

Vimentin is a novel AKT1 target mediating motility and invasion.

Zhu QS, Rosenblatt K, Huang KL, Lahat G, Brobey R, Bolshakov S, Nguyen T, Ding Z, Belousov R, Bill K, Luo X, Lazar A, Dicker A, Mills GB, Hung MC, Lev D

Oncogene.. 2011 January 2730 (4):457-70. Epub 09/20/2010.

Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.

Lahat G, Zhu QS, Huang KL, Wang S, Bolshakov S, Liu J, Torres K, Langley RR, Lazar AJ, Hung MC, Lev D

PloS one.. 2010 April 165 (4):e10105. Epub 04/16/2010.

Src family kinases mediate betel quid-induced oral cancer cell motility and could be a biomarker for early invasion in oral squamous cell carcinoma.

Chen JY, Hung CC, Huang KL, Chen YT, Liu SY, Chiang WF, Chen HR, Yen CY, Wu YJ, Ko JY, Jou YS

Neoplasia : an international journal for oncology research.. 2008 December 10 (12):1393-401. Epub 1900 01 01.

Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1 osteoblasts.

Kang HY, Cho CL, Huang KL, Wang JC, Hu YC, Lin HK, Chang C, Huang KE

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.. 2004 July 19 (7):1181-90. Epub 03/08/2004.