Sarah Hainer

  • Assistant Professor
  • Gene Expression and Cell Fate


Office: 412.624.6164
A527 Langley Hall
4249 Fifth Avenue
Pittsburgh, PA 15260
Figure 1. Diagram of promoter and enhancer regulatory regions. Promoter proximal antisense RNA (asRNA), coding gene (mRNA), enhancer RNAs (eRNAs) and nucleosome depleted regions (NDR) are labeled. Pink circles are nucleosomes and purple circles are RNAPII.

An unexpected finding from genome-scale studies is that the majority of the human genome is transcribed. Although protein-coding regions comprise only ~2% of the human genome, at least 75% is transcribed at detectable levels. These findings have led to a re-evaluation of the mammalian genome – if non-coding regions are transcribed, the resulting non-coding RNAs (ncRNAs) may have important functions. This possibility has tremendous ramifications for biomedical research, since clinical samples subjected to diagnostic sequencing are typically examined at only a subset of important genes, and only in their coding sequences.

ncRNAs are produced from many different regulatory regions in cells (Fig 1). Short ncRNA molecules expressed from within enhancer sequences, termed eRNAs, are thought to be necessary for enhancer looping and gene regulation. Promoter associated ncRNAs originating upstream from promoters (PROMPTs) have been identified in numerous eukaryotes, and mechanisms of their termination and degradation have been described. However, the transcriptional regulation and function of the majority of these ncRNA transcripts remain largely undefined.

One key regulatory mechanism shared among eukaryotes is the control of access to regulatory sequences by transcription factors through alteration of nucleosome occupancy or positioning. Nucleosome remodeling factors use the energy from ATP hydrolysis to reposition, deposit, or remove nucleosomes at regulatory regions by altering histone-DNA contacts. The actions of nucleosome remodeling factors are critical for transcription, DNA repair, and other essential cellular functions. Given their key roles in regulation of gene expression and genome integrity, it is perhaps not surprising that nucleosome remodeling factors are among the most commonly mutated or epigenetically silenced genes in human cancers and neurological disorders. However, the mechanisms by which loss of nucleosome remodeling factors function contributes to cancer and disease development are largely unknown.

Recently, we found that the embryonic stem (ES) cell-specific nucleosome remodeling complex esBAF, which occupies both enhancers and promoters, is required for regulating ncRNA expression throughout the ES cell genome (Fig 2). ES cells must carefully regulate the decision to either self-renew (proliferate as ES cells) or differentiate into precursors of the 200+ cell types found in adult humans and at the heart of this decision is the ES cell gene regulatory network, which is regulated by the coordinated efforts of numerous proteins including chromatin regulatory complexes such as esBAF. Determining the mechanism factors utilize to regulate the self-renewal- or differentiation-specific gene network is essential to uncover basic developmental processes and further our understanding of ES cell-based therapeutics.

Figure 2. esBAF represses ncRNA expression by promoting nucleosome occupancy flanking NDRs. (A-B) Heatmap of  strand-specific RNA-Seq showing transcripts generated antisense to TSSs (A) or surrounding gene distal DHSs (B) in control and Brg1 KD ES cells. These data show a large increase in the expression of transcripts generated in Brg1 KD cells relative to control. (C) Aggregation plot of MNase-Seq data showing nucleosome occupancy at gene distal DHSs in control and Brg1 KD ES cells. These data show a decrease in NDR-flanking nucleosome occupancy in Brg1 KD cells. (D) Fold change of Brg1 KD/control gene distal transcripts identified through RNA-Seq (left panel) and flanking nucleosome occupancy identified through MNase-Seq (right panel) paired and sorted. These data show that decreased flanking nucleosome occupancy (green) correlates with increased transcript production (yellow) in Brg1 KD cells.

The Hainer lab will address a number outstanding questions regarding transcription regulation in ES cells, utilizing a variety of molecular, cytological, and genomic techniques, through distinct but related projects. Specifically, we will determine (1) the network of nucleosome remodeling complexes regulating ncRNA expression, (2) how esBAF and other nucleosome remodeling complexes regulate higher order chromatin structure, (3) the functions of enhancer-specific ncRNAs in enhancer looping, gene regulation, and control of the ES cell state, and (4) the mechanisms underlying regulation of mRNAs by enhancer and promoter ncRNAs.

E-mail Lab

<p>C Viner, CA Ishak, J Johnson, NJ Walker, H Shi,

C Viner, CA Ishak, J Johnson, NJ Walker, H Shi, MK Sjoberg-Herrera, SY Shen, SM Lardo, DJ Adams, AC Ferguson-Smith, DD de Carvolho, SJ Hainer, TL Bailey, MM Hoffman. Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet. Genome Biology. 2024; 25(1):11.

<p><strong>DC Klein, SM Lardo, SJ Hainer. </strong

DC Klein, SM Lardo, SJ Hainer. The ncBAF complex regulates transcription in AML through H3K27ac sensing by BRD9. Cancer Research Communications. 2023.

DC Klein, SM Lardo, KN McCanne

DC Klein, SM Lardo, KN McCannell, SJ Hainer. FACT maintains pluripotency factor expression through proximal and gene-distal regulation in embryonic stem cells. BMC Biology. 2023; 21,167

DC Klein, K Troy, SA T

DC Klein, K Troy, SA Tripplehorn, SJ Hainer. The esBAF and ISW1 nucleosome remodeling complexes influence occupancy of overlapping dinucleosomes and fragile nucleosomes in murine embryonic stem cells. BMC Genomics. 2023; 24,201

H Zou, B Poore, EE Brown, J Qi

H Zou, B Poore, EE Brown, J Qian, B Xie, V Razskazovskiy, D Ayrapetian, E Asimakidou, V Sharma, S Xia, F Liu, A Chen, Y Guan, Z Li, S Wanggou, X Wu, O Saulnier, M Ly, W Fellows-Mayle, G Xi, T Tomita, AC Resnick, SC Mack, EH Raabe, CG Eberhart, D Sun, BE Stronach, S Agnihotri, G Kohanbash, S Lu, K Herrup, JN Rich, GK Gittes, A Broniscer, Z Hu, X Li, IF Pollack, RM Friedlander, SJ Hainer*, MD Taylor*, B Hu*. A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medullablastoma metastasis. Nature Cell Biology. 2023 Mar;25(3):493-507

C McCann, M Quinteros, I Adelugba, M Morgada, A

C McCann, M Quinteros, I Adelugba, M Morgada, AR Castelblanco, EJ Davis, A Lanzirotti, SJ Hainer, A Vila, P Cobine, JG Navea, T Padilla-Benavides. The mitochondrial Cu+ transporter PiC2 (Slc25a3) is a target of MTF1 required for development of skeletal muscle in vitro by contributing to cytochrome c oxidase metallation. Frontiers in Molecular Biosciences. 2022 Nov 9;9:1037941

SM Lardo and SJ Hainer

SM Lardo and SJ Hainer. Single cell factor localization on chromatin using ultra-low input cleavage under targets and release using nuclease. J. Vis. Exp. 2022; (180), e63536.

BJ Patty and SJ Hainer. &nbsp;

BJ Patty and SJ Hainer.  Transcription factor chromatin profiling genome-wide using uliCUT&RUN in single cells and individual blastocysts. Nature Protocols. 2021; 16:2633-2666

BJ Patty and SJ Hainer. Non-Coding RNAs and Nuc

BJ Patty and SJ Hainer. Non-Coding RNAs and Nucleosome Remodeling Complexes: An Intricate Regulatory Relationship. Biology 2020 August 6; 9(8): 213

K Troy, Y. Liu*, SJ Hainer*. PathSTORM: a road

K Troy, Y. Liu*, SJ Hainer*. PathSTORM: a road to early cancer detection. Molecular & Cellular Oncology. 2020

SJ Hainer* and CD Kaplan* Specialized RSC: subs

SJ Hainer* and CD Kaplan* Specialized RSC: substrate specificities for a conserved chromatin remodeler. BioEssays. 2020 July; 42(7):e2000002

J Xu, H Ma, H Ma, W Jiang, M Duan, S Zhao, C Ga

J Xu, H Ma, H Ma, W Jiang, M Duan, S Zhao, C Gao, E-R Hahm, SM Lardo, K Troy, M Sun, R Pai, DB Stolz, S Singh, RE Brand, DJ Hartman, J Hu, SJ Hainer*, Y Liu*. Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis. Nature Communications, 2020 April 20; 11(1): 1899

NA Fraunhoffer, N Agarwal, K Takeishi, A Ostrow

NA Fraunhoffer, N Agarwal, K Takeishi, A Ostrowska, AC l’Hortet, J Guzman-Lepe, K Morita, K Troy, WM Mars, S Paranjpe, GK Michalopoulos, A Bell, SJ Hainer, IJ Fox, A Soto-Gutierrez Cellular location of HNF4a is linked with terminal liver failure in humans. Hepatology Communications, 2020 April 21;

DC Klein and SJ Hainer. Chromatin Regulation an

DC Klein and SJ Hainer. Chromatin Regulation and Dynamics in Stem Cells. Current Topics in Developmental Biology, 2020;138:1-71

DC Klein and SJ Hainer. Genomic Methods in Prof

DC Klein and SJ Hainer. Genomic Methods in Profiling DNA Accessibility and Factor Localization. Chromosome Res, 2020 Mar; 28 (1): 69-85

C Tavera-Montanez*, SJ Hainer*, D Cangussu, SJV

C Tavera-Montanez*, SJ Hainer*, D Cangussu, SJV Gordon, Y Xiao, P Reyes-Gutierrez, AN Imbalzano, JG Navea, TG Fazzio, T Padilla-Benavides. The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper. FASEB J. 2019 Dec; 33(12):14556-14574

SJ Hainer, A&nbsp;

SJ Hainer, A Boskovic, KM McCannell, OJ Rando, TG Fazzio. Profiling of pluripotency factors in individual stem cells and early embryos. Cell. 2019 May 16;177(5):1319-1329.e11

SJ Hainer and TG Fazzio.&nbsp;High‐Resolution C

SJ Hainer and TG Fazzio. High‐Resolution Chromatin Profiling Using CUT&RUN. Curr Protoc Mol Biol. 2019 Jan 28:e85.

D Acharya,&nbsp;SJ&nbsp;Hainer

D Acharya, SJ Hainer, Y Yoon, F Wang, I Bach, JA Rivera-Perez, TG Fazzio. KAT-independent gene regulation by Tip60 promotes ESC self-renewal but not pluripotency. Cell Reports. 2017 19: 671-679


SJ Hainer, KN McCannell, J Yu, L Ee, LJ Zhu, OJ Rando, TG Fazzio. DNA methylation directs genomic localization of Mbd2 and Mbd3 in ES cells. Elife. 2016 Nov 16;5.

SJ Hainer and JA Martens. Regu

SJ Hainer and JA Martens. Regulation of chaperone binding and nucleosome dynamics by key residues within the globular domain of histone H3. Epigenetics & Chromatin. 2016 Apr 30;9:17.

SJ Hainer and TG Fazzio. Regul

SJ Hainer and TG Fazzio. Regulation of Nucleosome Architecture and Factor Binding Revealed by Nuclease Footprinting of the ESC Genome. Cell Reports. 2015 Oct 6;13(1):61-9

SJ Hainer, W Gu, BR Carone, BL

SJ Hainer, W Gu, BR Carone, BL Landry, OJ Rando, CC Mello, TG Fazzio. Suppression of pervasive noncoding transcription in embryonic stem cells by esBAF. Genes & Dev. 2015 Feb 15;29(4): 362-378

PB Chen, LJ Zhu, SJ Hainer, KN

PB Chen, LJ Zhu, SJ Hainer, KN McCannell, TG Fazzio. Unbiased chromatin accessibility profiling by RED-seq uncovers unique features of nucleosome variants in vivo. BMC Genomics. 2014 15:1104

BR Carone, JH Hung, SJ Hainer,

BR Carone, JH Hung, SJ Hainer, MT Chou, DM Carone, Z Weng, TG Fazzio, OJ Rando. High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm. Dev Cell. 2014 Jul 14: 11-22

SJ Hainer, BA Charsar, SB Cohe

SJ Hainer, BA Charsar, SB Cohen, JA Martens. Identification of mutant versions of the Spt16 histone chaperone that are defective for transcription-coupled nucleosome occupancy in Saccharomyces cerevisiae. G3 (Bethesda). 2012 May 2:555-567

JA Pruneski, SJ Hainer, KO Pet

JA Pruneski, SJ Hainer, KO Petrov, JA Martens. The Paf1 complex represses SER3 transcription in Saccharomyces cerevisiae by facilitating intergenic transcription-dependent nucleosome occupancy of the SER3 promoter. Eukaryotic Cell. 2011 Oct;10(10):1283-94

SJ Hainer and JA Martens. Iden

SJ Hainer and JA Martens. Identification of histone mutations that are required for transcription-coupled nucleosome occupancy. Mol Cell Biol. 2011 Sep;31(17):3557-68

SJ Hainer and JA Martens. Tran

SJ Hainer and JA Martens. Transcription of ncDNA across regulatory sequences: many roads lead to local gene regulation. Transcription. 2011 May/June 2(3):120-123

SJ Hainer, JA Pruneski, RD Mit

SJ Hainer, JA Pruneski, RD Mitchell, R Monteverde, JA Martens. Intergenic transcription causes repression by directing nucleosome assembly. Genes & Dev. 2011 Jan 1;25(1):29-40
Dr. Hainer received her Ph.D. in 2012 from the University of Pittsburgh for work on gene regulation in the laboratory of Joe Martens, performed her postdoctoral studies on chromatin regulation of coding and non-coding RNAs in stem cells at the University of Massachusetts Medical School in the laboratory of Tom Fazzio, and joined the department in 2018.

2021                   Iris Marion Young Award, University of Pittsburgh

2020                   Most Valuable Professor”, Awarded by University of Pittsburgh Women’s Diving Team

2020                  University nominee for Pew Biomedical Scholar

2019                  University nominee for Edward Mallinckrodt, Jr Foundation Scholar Program

2019                  University nominee for Johnson&Johnson WiSTEM2D Scholars Award

2019                  University nominee for Packard Fellowships for Science and Engineering

2018                  Nominee for Arnold and Mabel Beckman Foundation Young Investigator Award

2016 - 2019      Special Fellow, Leukemia and Lymphoma Society

2013 - 2016      Fellow, Leukemia and Lymphoma Society

2012 - 2013      T32 Institutional Training Grant Postdoctoral Fellowship