Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein

Wang, Mingyu; Zhang, Chunmiao; Zhou, Haihong; Ge, Zhong-Bo; Su, Chen-Chen; Lou, Zi-Hao; Zhang, Xinyun; Xu, Taotao; Li, Siyi; Zhu, Li; Zhou, Yuan‐Guo; Wu, Yi; Ji, Shang‐Rong

doi:10.1016/j.jbc.2022.102160

Cited by 8 publications

(9 citation statements)

References 40 publications

(62 reference statements)

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“…Furthermore, by examining the activities of E1-promoter hybrids and the related epigenetic alterations, we show that E1 coordinates with the promoter of CRP to control its variable expression across tissues and species. These findings thus point to an intriguing form of molecular evolution in which expression-changing mutations in distal regulatory elements start a process of functional selection that involves interaction between distal/proximal regulatory alterations and activity-changing coding mutations ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Biological significance of C-reactive protein, the ancient acute phase functionary

Bhattacharya,

Munshi

2023

Front. Immunol.

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C-reactive protein (CRP) is one of the major members of the family of acute phase proteins (APP). Interest in this CRP was the result of a seminal discovery of its pattern of response to pneumococcal infection in humans. CRP has the unique property of reacting with phosphocholine-containing substances, such as pneumococcal C-polysaccharide, in the presence of Ca2+. The attention regarding the origin of CRP and its multifunctionality has gripped researchers for several decades. The reason can be traced to the integrated evolution of CRP in the animal kingdom. CRP has been unequivocally listed as a key indicator of infectious and inflammatory diseases including autoimmune diseases. The first occurrence of CRP in the evolutionary ladder appeared in arthropods followed by molluscs and much later in the chordates. The biological significance of CRP has been established in the animal kingdom starting from invertebrates. Interestingly, the site of synthesis of CRP is mainly the liver in vertebrates, while in invertebrates it is located in diverse tissues. CRP is a multifunctional player in the scenario of innate immunity. CRP acts as an opsonin in the area of complement activation and phagocytosis. Interestingly, CRP upregulates and downregulates both cytokine production and chemotaxis. Considering various studies of CRP in humans and non-human animals, it has been logically proposed that CRP plays a common role in animals. CRP also interacts with Fcγ receptors and triggers the inflammatory response of macrophages. CRP in other animals such as primates, fish, echinoderms, arthropods, and molluscs has also been studied in some detail which establishes the evolutionary significance of CRP. In mammals, the increase in CRP levels is an induced response to inflammation or trauma; interestingly, in arthropods and molluscs, CRP is constitutively expressed and represents a major component of their hemolymph. Investigations into the primary structure of CRP from various species revealed the overall relatedness between vertebrate and invertebrate CRP. Invertebrates lack an acquired immune response; they are therefore dependent on the multifunctional role of CRP leading to the evolutionary success of the invertebrate phyla.

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Section: Discussionmentioning

confidence: 99%

Biological significance of C-reactive protein, the ancient acute phase functionary

Bhattacharya,

Munshi

2023

Front. Immunol.

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“…Remarkably, a recent study performed in humans identified an enhancer (E1) located 37.7 Kb upstream of the CRP promoter. Transcription factors STAT3, C/EBP-β, and USF1/2 appear to mediate the regulatory effects of E1 acting in conjunction with CRP proximal promoter for the acute phase induction by IL-6 and IL-1β of human CRP ( 16 , 25 , 26 , 60 ). Furthermore, the constitutive expression of human CRP at the basal state seems to be mediated by promoter binding of transcription factors such as HNF-1, HNF-3 and OCT-1 ( 21 , 56 ).…”

Section: Discussionmentioning

confidence: 99%

“…While HNF-1, HNF-3, and OCT-1 transcriptions factors are involved in the regulation of basal CRP expression levels ( 20 – 22 ), the induction of the acute phase expression of CRP is mediated by the effect of cytokines, particularly IL-6, IL-1β and TNF-α, through the activation of STAT3, NF-kB and C/EBP-β transcription factors ( 16 , 19 , 23 – 25 ). In this regard, a recent study in human Hep3B cells identified an enhancer upstream of the CRP promoter enriched in binding sites for STAT3 and C/EBP-β with a major impact on the acute phase induction of CRP expression ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver

Hernández-Banqué,

Jové-Juncà,

Crespo-Piazuelo

et al. 2023

Front. Immunol.

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C-reactive protein (CRP) is an evolutionary highly conserved protein. Like humans, CRP acts as a major acute phase protein in pigs. While CRP regulatory mechanisms have been extensively studied in humans, little is known about the molecular mechanisms that control pig CRP gene expression. The main goal of the present work was to study the regulatory mechanisms and identify functional genetic variants regulating CRP gene expression and CRP blood levels in pigs. The characterization of the porcine CRP proximal promoter region revealed a high level of conservation with both cow and human promoters, sharing binding sites for transcription factors required for CRP expression. Through genome-wide association studies and fine mapping, the most associated variants with both mRNA and protein CRP levels were localized in a genomic region 39.3 kb upstream of CRP. Further study of the region revealed a highly conserved putative enhancer that contains binding sites for several transcriptional regulators such as STAT3, NF-kB or C/EBP-β. Luciferase reporter assays showed the necessity of this enhancer-promoter interaction for the acute phase induction of CRP expression in liver, where differences in the enhancer sequences significantly modified CRP activity. The associated polymorphisms disrupted the putative binding sites for HNF4α and FOXA2 transcription factors. The high correlation between HNF4α and CRP expression levels suggest the participation of HNF4α in the regulatory mechanism of porcine CRP expression through the modification of its binding site in liver. Our findings determine, for the first time, the relevance of a distal regulatory element essential for the acute phase induction of porcine CRP in liver and identify functional polymorphisms that can be included in pig breeding programs to improve immunocompetence.

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“…The transcriptional regulation of macrophage colony‐stimulating factor (M‐CSF), a growth factor linked to inflammation and Aβ peptide formation in microglia, is orchestrated by C/EBPβ 59,60 . C‐reactive protein possesses the capability to activate the complement system and harbors a binding site for C/EBPβ within its promoter 61 . Myeloperoxidase similarly contains a promoter site for C/EBPβ 62 .…”

Section: The Molecular Pathway Mechanisms Of C/ebpβ Regulating the Ir...mentioning

confidence: 99%

“… 59 , 60 C‐reactive protein possesses the capability to activate the complement system and harbors a binding site for C/EBPβ within its promoter. 61 Myeloperoxidase similarly contains a promoter site for C/EBPβ. 62 The degradation of C/EBPβ in microglia resulted in the inhibition of neuroinflammation.…”

Section: The Molecular Pathway Mechanisms Of C/ Ebpβ ...mentioning

confidence: 99%

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease

Yao,

Long,

et al. 2024

CNS Neurosci Ther

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BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β‐amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.AimsSeveral studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.MethodsA systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case–control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.ResultsOverexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ‐secretase, apolipoprotein E4 (APOE4), acidic leucine‐rich nuclear phosphoprotein‐32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).DiscussionThe correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).ConclusionThe overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.

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Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein

Cited by 8 publications

References 40 publications

Biological significance of C-reactive protein, the ancient acute phase functionary

Biological significance of C-reactive protein, the ancient acute phase functionary

Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease

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