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Intrinsically dysregulated cellular stress signaling genes and gene networks in postpartum depression

Molecular Psychiatry volume 28, pages 3023–3032 (2023)Cite this article

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Abstract

Postpartum depression (PPD) is a leading cause of morbidity and mortality among women. Clinically, the administration and withdrawal of supraphysiologic estradiol and progesterone (E2 + P) can cause affective symptom reoccurrence in women with a history of PPD, but not matched controls. To investigate the cellular basis underlying this differential affective response, lymphoblastoid cell lines (LCLs) were derived from women with and without past PPD and compared transcriptomically in hormone conditions mimicking pregnancy and parturition: supraphysiologic E2 + P-addback; supraphysiologic E2 + P-withdrawal; and no added E2 + P (Baseline). RNA-sequencing identified unique differentially expressed genes (DEGs) in all hormone conditions, but the majority tended to be downregulated in PPD and observed in E2 + P-addback. Two of these DEGs were evolutionarily conserved cellular stress regulators: IMPACT, an integrative response protein maintaining translational homeostasis, and WWTR1, a transcriptional coactivator in the ‘Hippo’ pathway mediating cell proliferation and survival. Correspondingly, significant gene network modules were linked to cell cycle progression, estrogen response, and immune dysregulation, suggesting innate differences in intracellular signaling in PPD. In certain hormone conditions, PPD LCLs displayed increased GATA3 expression (an upstream regulator of IMPACT and WWTR1) and differentially phosphorylated eiF2α (the ultimate downstream target of IMPACT). Taken together, these transcriptomic data primarily implicate innately dysregulated cellular responses as potentially influencing mood and/or escalating PPD risk. Furthermore, the intrinsic downregulation of IMPACT’s translation and WWTR1’s transcription networks may suggest a novel link between PPD and a compromised ability to maintain homeostasis in the context of cellular stress occurring during pregnancy and parturition.

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Fig. 1: Transcriptomics reveal differentially expressed genes (DEGs) in PPD LCLs compared to Controls in all steroid hormone conditions (HCs), identifying the most FDR-significant DEGs in E2+P-Addback and a bias toward transcript downregulation in PPD.
Fig. 2: IMPACT and WWTR1 (TAZ), cellular stress signaling genes, are decreased in PPD LCLs.
Fig. 3: Transcription factors GATA3 and MYC, and related gene networks, are dysregulated in PPD.
Fig. 4: eiF2α, a downstream target of IMPACT, is differentially phosphorylated at baseline in PPD LCLs.
Fig. 5: Weighted Gene Correlation Network Analysis (WGCNA) uncovers eight PPD significant modules with enriched functions including IL-2/STAT5, GATA, MYC, estrogen response, and E2F cell cycle regulation.

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Acknowledgements

We would like to thank Cheryl Marietta, Longina Akhtar, Howard Li, Alan Meyers, and Damien Islek of NIH/NIAAA for their technical assistance, support, and expertize in conducting this study. In addition, we thank Erin Richardson and Laura Lundegard of UNC for assisting with study administration and specimen collection. This work was written as part of PJS’s and DG’s official duties as government employees. This research was supported by the Office of Clinical Research Bench to Bedside Program Funds Award #480670 and the Intramural Research Programs of the NIMH/NIH and NIAAA/NIH; Protocols 95-M-0097 and 03-M-0138; NIMH Project #MH002865 and NIAAA Project #AA000301. Extramural funding from the Foundation of Hope, Brain & Behavior Research Foundation, and NIH R21MH101409. Clinical Trial: NCT01762943.

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  1. Behavioral Endocrinology Branch, NIMH, Bldg. 10CRC, Room 25330, 10 Center Drive MSC 1277, Bethesda, 20892-1277, MD, USA

    Sarah A. Rudzinskas, Allison C. Goff, Maria A. Mazzu & Peter J. Schmidt

  2. Laboratory of Neurogenetics, NIAAA, Bethesda, MD, USA

    Sarah A. Rudzinskas, Allison C. Goff, Maria A. Mazzu & David Goldman

  3. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    Crystal Edler Schiller, Samantha Meltzer-Brody & David R. Rubinow

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Contributions

SR designed, planned, performed, and analyzed the experiments and data. AG contributed the computational framework for data analysis. MM helped perform the experiments. CES, and SM-B designed the protocols that provided the clinical samples used. DR, PS, and DG conceived the research questions and contributed to the interpretation of the results. SR led the drafting of the paper in direct consultation with PS and DG. All authors gave critical input and approved the final paper.

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The authors declare no competing interests or financial support regarding this paper. SM-B receives grant support from Janssen Research and Development and Sage Therapeutics, Inc., awarded to the University of North Carolina (Chapel Hill, NC), but these grants are outside the submitted work.

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Rudzinskas, S.A., Goff, A.C., Mazzu, M.A. et al. Intrinsically dysregulated cellular stress signaling genes and gene networks in postpartum depression. Mol Psychiatry 28, 3023–3032 (2023). https://doi.org/10.1038/s41380-023-01985-5

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