Zihao Deng

All Publications

• Integrative analysis reveals marker genes for intestinal mucosa barrier repairing in clinical patients. iScience Zhao, X. H., Zhao, P., Deng, Z., Yang, T., Qi, Y. X., An, L. Y., Sun, D. L., He, H. Y. 2023; 26 (6): 106831

  Abstract

  This study aims to identify biomarkers of intestinal repair and provide potential therapeutic clues for improving functional recovery and prognostic performance after intestinal inflammation or injury. Here, we conducted a large-scale screening of multiple transcriptomic and scRNA-seq datasets of patients with inflammatory bowel disease (IBD), and identified 10 marker genes that potentially contribute to intestinal barrier repairing: AQP8, SULT1A1, HSD17B2, PADI2, SLC26A2, SELENBP1, FAM162A, TNNC2, ACADS, and TST. Analysis of a published scRNA-seq dataset revealed that expression of these healing markers were specific to absorptive cell types in intestinal epithelium. Furthermore, we conducted a clinical study where 11 patients underwent ileum resection demonstrating that upregulation of post-operative AQP8 and SULT1A1 expression were associated with improved recovery of bowel functions after surgery-induced intestinal injury, making them confident biomarkers of intestinal healing as well as potential prognostic markers and therapeutic targets for patients with impaired intestinal barrier functions.

  View details for DOI 10.1016/j.isci.2023.106831

  View details for PubMedID 37250791

  View details for PubMedCentralID PMC10212979

• Dysregulation of Grainyhead-like 3 expression causes widespread developmental defects. Developmental dynamics : an official publication of the American Association of Anatomists Deng, Z., Butt, T., Arhatari, B. D., Darido, C., Auden, A., Swaroop, D., Partridge, D. D., Haigh, K., Nguyen, T., Haigh, J. J., Carpinelli, M. R., Jane, S. M. 2023; 252 (5): 647-667

  Abstract

  The gene encoding the transcription factor, Grainyhead-like 3 (Grhl3), plays critical roles in mammalian development and homeostasis. Grhl3-null embryos exhibit thoraco-lumbo-sacral spina bifida and soft-tissue syndactyly. Additional studies reveal that these embryos also exhibit an epidermal proliferation/differentiation imbalance. This manifests as skin barrier defects resulting in peri-natal lethality and defective wound repair. Despite these extensive analyses of Grhl3 loss-of-function models, the consequences of gain-of-function of this gene have been difficult to achieve.In this study, we generated a novel mouse model that expresses Grhl3 from a transgene integrated in the Rosa26 locus on an endogenous Grhl3-null background. Expression of the transgene rescues both the neurulation and skin barrier defects of the knockout mice, allowing survival into adulthood. Despite this, the mice are not normal, exhibiting a range of phenotypes attributable to dysregulated Grhl3 expression. In mice homozygous for the transgene, we observe a severe Shaker-Waltzer phenotype associated with hearing impairment. Micro-CT scanning of the inner ear revealed profound structural alterations underlying these phenotypes. In addition, these mice exhibit other developmental anomalies including hair loss, digit defects, and epidermal dysmorphogenesis.Taken together, these findings indicate that diverse developmental processes display low tolerance to dysregulation of Grhl3.

  View details for DOI 10.1002/dvdy.565

  View details for PubMedID 36606449

• Inhibition of retinoic acid signaling impairs cranial and spinal neural tube closure in mice lacking the Grainyhead-like 3 transcription factor. Biochemical and biophysical research communications Deng, Z., Carpinelli, M. R., Butt, T., Magor, G. W., Perkins, A. C., Jane, S. M. 2022; 635: 244-251

  Abstract

  Neural tube closure is a dynamic morphogenic event in early embryonic development. Perturbations of this process through either environmental or genetic factors induce the severe congenital malformations known collectively as neural tube defects (NTDs). Deficiencies in maternal folate intake have long been associated with NTDs, as have mutations in critical neurulation genes that include the Grainyhead-like 3 (Grhl3) gene. Mice lacking this gene exhibit fully penetrant thoraco-lumbo-sacral spina bifida and a low incidence of exencephaly. Previous studies have shown that exposure of pregnant mice carrying hypomorphic Grhl3 alleles to exogenous retinoic acid (RA) increases the incidence and severity of NTDs in their offspring. Here, we demonstrate that inhibition of RA signaling using a high affinity pan-RA receptor antagonist administered to pregnant mice at E7.5 induces fully penetrant exencephaly and more severe spina bifida in Grhl3-null mice. Later administration, although prior to neural tube closure has no effect. Similarly, blockade of RA in the context of reduced expression of Grhl2, a related gene known to induce NTDs, has no effect. Taken together, these findings provide new insights into the complexities of the interplay between RA signaling and Grhl3-induced neurulation.

  View details for DOI 10.1016/j.bbrc.2022.10.060

  View details for PubMedID 36283337

• Germline Missense Variants in <i>SH2B3</i> Underpin Platelet Count Variation and Inherited MPN Butler, L., Lee, C., Magor, G., Morris, R., Tallack, M., Lam, C., Ivey, A., Lin, J., Deng, Z., Grigg, A., Mason, J., Perchard, M., Weston, H., Cummings, N., Brooks, A., Babon, J. J., Murphy, A. J., Salmon, J. M., Perkins, A. AMER SOC HEMATOLOGY. 2022: 1093-1094

  View details for DOI 10.1182/blood-2022-159416

  View details for Web of Science ID 000893223201040

• Grainyhead-like transcription factors: guardians of the skin barrier. Veterinary dermatology Deng, Z., Cangkrama, M., Butt, T., Jane, S. M., Carpinelli, M. R. 2021; 32 (6): 553-e152

  Abstract

  There has been selective pressure to maintain a skin barrier since terrestrial animals evolved 360 million years ago. These animals acquired an unique integumentary system with a keratinized, stratified, squamous epithelium surface barrier. The barrier protects against dehydration and entry of microbes and toxins. The skin barrier centres on the stratum corneum layer of the epidermis and consists of cornified envelopes cemented by the intercorneocyte lipid matrix. Multiple components of the barrier undergo cross-linking by transglutaminase (TGM) enzymes, while keratins provide additional mechanical strength. Cellular tight junctions also are crucial for barrier integrity. The grainyhead-like (GRHL) transcription factors regulate the formation and maintenance of the integument in diverse species. GRHL3 is essential for formation of the skin barrier during embryonic development, whereas GRHL1 maintains the skin barrier postnatally. This is achieved by transactivation of Tgm1 and Tgm5, respectively. In addition to its barrier function, GRHL3 plays key roles in wound repair and as an epidermal tumour suppressor. In its former role, GRHL3 activates the planar cell polarity signalling pathway to mediate wound healing by providing directional migration cues. In squamous epithelium, GRHL3 regulates the balance between proliferation and differentiation, and its loss induces squamous cell carcinoma (SCC). In the skin, this is mediated through increased expression of MIR21, which reduces the expression levels of GRHL3 and its direct target, PTEN, leading to activation of the PI3K-AKT signalling pathway. These data position the GRHL family as master regulators of epidermal homeostasis across a vast gulf of evolutionary history.

  View details for DOI 10.1111/vde.12956

  View details for PubMedID 33843098

• Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure. Disease models & mechanisms Carpinelli, M. R., de Vries, M. E., Auden, A., Butt, T., Deng, Z., Partridge, D. D., Miles, L. B., Georgy, S. R., Haigh, J. J., Darido, C., Brabletz, S., Brabletz, T., Stemmler, M. P., Dworkin, S., Jane, S. M. 2020; 13 (3)

  Abstract

  Cleft lip and palate are common birth defects resulting from failure of the facial processes to fuse during development. The mammalian grainyhead-like (Grhl1-3) genes play key roles in a number of tissue fusion processes including neurulation, epidermal wound healing and eyelid fusion. One family member, Grhl2, is expressed in the epithelial lining of the first pharyngeal arch in mice at embryonic day (E)10.5, prompting analysis of the role of this factor in palatogenesis. Grhl2-null mice die at E11.5 with neural tube defects and a cleft face phenotype, precluding analysis of palatal fusion at a later stage of development. However, in the first pharyngeal arch of Grhl2-null embryos, dysregulation of transcription factors that drive epithelial-mesenchymal transition (EMT) occurs. The aberrant expression of these genes is associated with a shift in RNA-splicing patterns that favours the generation of mesenchymal isoforms of numerous regulators. Driving the EMT perturbation is loss of expression of the EMT-suppressing transcription factors Ovol1 and Ovol2, which are direct GRHL2 targets. The expression of the miR-200 family of microRNAs, also GRHL2 targets, is similarly reduced, resulting in a 56-fold upregulation of Zeb1 expression, a major driver of mesenchymal cellular identity. The critical role of GRHL2 in mediating cleft palate in Zeb1-/- mice is evident, with rescue of both palatal and facial fusion seen in Grhl2-/-;Zeb1-/- embryos. These findings highlight the delicate balance between GRHL2/ZEB1 and epithelial/mesenchymal cellular identity that is essential for normal closure of the palate and face. Perturbation of this pathway may underlie cleft palate in some patients.

  View details for DOI 10.1242/dmm.042218

  View details for PubMedID 32005677

  View details for PubMedCentralID PMC7104862