STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses

Abstract Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (...

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Autores principales:	Ori Scott, Kyle Lindsay, Steven Erwood, Antonio Mollica, Chaim M. Roifman, Ronald D. Cohn, Evgueni A. Ivakine
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/f8847bc7541a4ab68fbd2ae0e0ec203f
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spelling	oai:doaj.org-article:f8847bc7541a4ab68fbd2ae0e0ec203f2021-12-02T15:54:59ZSTAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses10.1038/s41525-021-00196-72056-7944https://doaj.org/article/f8847bc7541a4ab68fbd2ae0e0ec203f2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00196-7https://doaj.org/toc/2056-7944Abstract Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype–phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenous STAT1 gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNα or IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modeling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with various STAT1 mutations, adding to global efforts in establishing STAT1 GOF genotype–phenotype correlation and enhancing our understanding of disease pathogenesis.Ori ScottKyle LindsaySteven ErwoodAntonio MollicaChaim M. RoifmanRonald D. CohnEvgueni A. IvakineNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Ori Scott Kyle Lindsay Steven Erwood Antonio Mollica Chaim M. Roifman Ronald D. Cohn Evgueni A. Ivakine STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
description	Abstract Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype–phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenous STAT1 gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNα or IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modeling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with various STAT1 mutations, adding to global efforts in establishing STAT1 GOF genotype–phenotype correlation and enhancing our understanding of disease pathogenesis.
format	article
author	Ori Scott Kyle Lindsay Steven Erwood Antonio Mollica Chaim M. Roifman Ronald D. Cohn Evgueni A. Ivakine
author_facet	Ori Scott Kyle Lindsay Steven Erwood Antonio Mollica Chaim M. Roifman Ronald D. Cohn Evgueni A. Ivakine
author_sort	Ori Scott
title	STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
title_short	STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
title_full	STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
title_fullStr	STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
title_full_unstemmed	STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
title_sort	stat1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f8847bc7541a4ab68fbd2ae0e0ec203f
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STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses

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