Zi Hao Zheng

All Publications

• Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development. Science immunology Mohammed, A., Wang, W., Arreola, M., Solomon, B. D., Slepicka, P. F., Hubka, K. M., Nguyen, H. D., Zheng, Z., Chavez, M. G., Yeh, C. Y., Kim, D. K., Ma, M. R., Martin, E., Li, L., Pasca, A. M., Winn, V. D., Gifford, C. A., Kedlian, V. R., Park, J. E., Khatri, P., Hollander, G. A., Roncarolo, M. G., Sebastiano, V., Teichmann, S. A., Gentles, A. J., Weinacht, K. G. 2025; 10 (107): eado4720

  Abstract

  Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving thymic epithelial differentiation remain incompletely understood. Here, we elucidated pathways instructing human thymic epithelial cell development in the context of other anterior foregut-derived organs. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of other anterior foregut-derived organs. Thymic cortex and medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored the effects of type I and II interferons on thymic epithelial progenitor differentiation from induced pluripotent stem cells. Type II interferon was essential for expressing proteasome and antigen-presenting molecules, whereas type I or II interferons were essential for inducing different cytokines in thymic epithelial progenitor cells. Our findings suggest that interferons are critical to cortical and medullary thymic epithelial cell differentiation.

  View details for DOI 10.1126/sciimmunol.ado4720

  View details for PubMedID 40315299

• Rewiring of SINE-MIR enhancer topology and Esrrb modulation in expanded and naive pluripotency GENOME BIOLOGY Cipta, N., Zeng, Y., Wong, K., Zheng, Z., Yi, Y., Warrier, T., Teo, J., Teo, J., Kok, Y., Bi, X., Taneja, R., Ong, D., Xu, J., Ginhoux, F., Li, H., Liou, Y., Loh, Y. 2025; 26 (1): 107

  Abstract

  The interplay between 3D genomic structure and transposable elements (TE) in regulating cell state-specific gene expression program is largely unknown. Here, we explore the utilization of TE-derived enhancers in naïve and expanded pluripotent states by integrative analysis of genome-wide Hi-C-defined enhancer interactions, H3K27ac HiChIP profiling and CRISPR-guided TE proteomics landscape.We find that short interspersed nuclear elements (SINEs) are the more involved TEs in the active chromatin and 3D genome architecture. In particular, mammalian-wide interspersed repeat (MIR), a SINE family member, is highly associated with naïve-specific genomic interactions compared to the expanded state. Primarily, in the naïve pluripotent state, MIR enhancer is co-opted by ESRRB for naïve-specific gene expression program. This ESRRB and MIR enhancer interaction is crucial for the formation of loops that build a network of enhancers and super-enhancers regulating pluripotency genes. We demonstrate that loss of a ESRRB-bound MIR enhancer impairs self-renewal. We also find that MIR is co-bound by structural protein complex, ESRRB-YY1, in the naïve pluripotent state.Altogether, our study highlights the topological regulation of ESRRB on MIR in the naïve potency state.

  View details for DOI 10.1186/s13059-025-03577-8

  View details for Web of Science ID 001478091100003

  View details for PubMedID 40296153

  View details for PubMedCentralID PMC12036290

• Accelerating Immune Reconstitution in HSCT Patients through iPSC-Derived Thymic Epithelial Cells Mohammed, A., Hanh Dan Nguyen, Hubka, K., Wang, W., Slepicka, P., Solomon, B., Arreola, M., Zheng, Z., Gentles, A., Weinacht, K. G. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186901

  View details for Web of Science ID 001159306701217

• SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates NUCLEIC ACIDS RESEARCH Warrier, T., El Farran, C., Zeng, Y., Ho, B., Bao, Q., Zheng, Z., Bi, X., Ng, H., Ong, D., Chu, J., Sanyal, A., Fullwood, M., Collins, J. J., Li, H., Xu, J., Loh, Y. 2022; 50 (13): 7326-7349

  Abstract

  SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene 'islands' that drive differentiation to other lineages. The 'unearthing' of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.

  View details for DOI 10.1093/nar/gkac531

  View details for Web of Science ID 000819499200001

  View details for PubMedID 35776115

  View details for PubMedCentralID PMC9303280

• Chromatin Regulation in Development: Current Understanding and Approaches STEM CELLS INTERNATIONAL Zheng, Z., Sam, T., Zeng, Y., Chu, J., Loh, Y. 2021; 2021: 8817581

  Abstract

  The regulation of mammalian stem cell fate during differentiation is complex and can be delineated across many levels. At the chromatin level, the replacement of histone variants by chromatin-modifying proteins, enrichment of specific active and repressive histone modifications, long-range gene interactions, and topological changes all play crucial roles in the determination of cell fate. These processes control regulatory elements of critical transcriptional factors, thereby establishing the networks unique to different cell fates and initiate waves of distinctive transcription events. Due to the technical challenges posed by previous methods, it was difficult to decipher the mechanism of cell fate determination at early embryogenesis through chromatin regulation. Recently, single-cell approaches have revolutionised the field of developmental biology, allowing unprecedented insights into chromatin structure and interactions in early lineage segregation events during differentiation. Here, we review the recent technological advancements and how they have furthered our understanding of chromatin regulation during early differentiation events.

  View details for DOI 10.1155/2021/8817581

  View details for Web of Science ID 000620227200001

  View details for PubMedID 33603792

  View details for PubMedCentralID PMC7872760

• Defining Essential Enhancers for Pluripotent Stem Cells Using a Features-Oriented CRISPR-Cas9 Screen CELL REPORTS Wang, H., Warrier, T., Farran, C. A., Zheng, Z., Xing, Q., Fullwood, M. J., Zhang, L., Li, H., Xu, J., Lim, T., Loh, Y. 2020; 33 (4): 108309

  Abstract

  cis-regulatory elements (CREs) regulate the expression of genes in their genomic neighborhoods and influence cellular processes such as cell-fate maintenance and differentiation. To date, there remain major gaps in the functional characterization of CREs and the identification of their target genes in the cellular native environment. In this study, we perform a features-oriented CRISPR-utilized systematic (FOCUS) screen of OCT4-bound CREs using CRISPR-Cas9 to identify functional enhancers important for pluripotency maintenance in mESCs. From the initial 235 candidates tested, 16 CREs are identified to be essential stem cell enhancers. Using RNA-seq and genomic 4C-seq, we further uncover a complex network of candidate CREs and their downstream target genes, which supports the growth and self-renewal of mESCs. Notably, an essential enhancer, CRE111, and its target, Lrrc31, form the important switch to modulate the LIF-JAK1-STAT3 signaling pathway.

  View details for DOI 10.1016/j.celrep.2020.108309

  View details for Web of Science ID 000582721000009

  View details for PubMedID 33113365