The cervix-specific proteome

The cervix transcriptome

Transcriptome analysis of the cervix can be visualized with regard to the specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the cervix compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

• Tissue enriched: At least four-fold higher mRNA level in cervix compared to any other tissues.
• Group enriched: At least four-fold higher average mRNA level in a group of 2-5 tissues compared to any other tissue.
• Tissue enhanced: At least four-fold higher mRNA level in cervix compared to the average level in all other tissues.

Distribution, on the other hand, visualizes how many genes have, or do not have, detectable levels (nTPM≥1) of transcribed mRNA molecules in the cervix compared to other tissues. As evident in Table 1, all genes elevated in cervix are categorized as:

• Detected in single: Detected in a single tissue
• Detected in some: Detected in more than one but less than one-third of tissues
• Detected in many: Detected in at least a third but not all tissues
• Detected in all: Detected in all tissues

Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in cervix as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (nTPM≥1) in cervix as well as in all other tissues.

As shown in Figure 1, 176 genes show some level of elevated expression in cervix compared to other tissues. The three categories of genes with elevated expression in cervix compared to other organs are shown in Table 1.

Table 1. The number of genes in the subdivided categories of elevated expression in cervix.

Protein expression of genes elevated in cervix

In-depth analysis of the elevated genes in cervix using antibody-based protein profiling allowed us to visualize where these proteins are expressed within the cervix, including glandular cells, stromal cells and squamous epithelial cells.

Proteins related to secreted expression in cervix

The cervical mucus has several functions including acting as a protective barrier and preventing bacteria from entering the uterine body. MUC16 is expressed in the cervix and is thought to be involved in forming a barrier protecting from pathogens. SLPI, secretory leukocyte peptidase inhibitor, is another protein that is found in cervical mucus with antimicrobial properties. WFDC2, a protease inhibitor with antiviral properties, is highly expressed in cervical mucus.

MUC16
SLPI
WFDC2

Proteins related to expression in squamous epithelial cells in cervix

Examples of proteins with elevated expression in the squamous epithelium of cervix (ectocervix) include TMPRSS11D, a membrane serine protease involved in mucous membrane host defense, involucrin, IVL, a cytoplasmic structural protein which makes the epithelium resistant to mechanical stress and damage, and estrogen receptor 1, ESR1, which is a nuclear receptor for the hormone estrogen, important for sexual development and reproductive function. Since estrogen is essential for the regulation of the entire female reproductive system, ESR1 is also expressed in the other tissues within the cervix, as well as other female reproductive tissues.

TMPRSS11D
IVL
ESR1

Proteins related to expression in stromal cells in cervix

The cervical stroma is composed of smooth muscle fibers embedded in collagen. Examples of genes with elevated expression in cervical stroma cells include COL1A2, COL3A1 and HOXA11. COL1A2 and COL3A1 are two types of collagen fiber proteins (type I and III) that bind the stromal tissue together. HOXA11 is a nuclear transcription factor that regulates the expression of genes involved in morphogenesis and cell differentiation.

COL1A2
COL3A1
HOXA11

Proteins related to expression in glandular cells in cervix

Examples of proteins expressed in cervical glands (endocervix) include ASRGL1, an asparaginase enzyme, MSX1, a transcriptional repressor, and BPIFB1, a secreted antimicrobial peptide believed to be involved in innate immune responses against invasive vaginal bacteria.

ASRGL1
MSX1
BPIFB1

Gene expression shared between the cervix and other tissues

There are 42 group enriched genes expressed in cervix. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including cervix, compared to all other tissues.

To illustrate the relation of cervix tissue to other tissue types, a network plot was generated, displaying the number of genes with a shared expression between different tissue types.

Figure 2. An interactive network plot of the cervix enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of cervix enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 4 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

Cervix shares most group enriched gene expression with other mucosal tissues, characterized by epithelium layers and mucus-producing glands, such as the salivary gland, esophagus and vagina. Such genes are exemplified above in the analysis of elevated genes in cervical squamous epithelial cells and glandular cells. Cervix also shares some group enriched gene expression with endometrium. An example of a group enriched gene with shared expression in the cervix and endometrium is nuclear progesterone receptor, PGR, which is highly expressed during the secretory phase of the menstrual cycle and plays a central role in reproductive events, expressed in both glandular and stromal cells.

PGR - Cervix
PGR - Endometrium

Cervix also shares some group enriched gene expression with epididymis. Mammaglobin-B, SCGB2A1, binds androgens and other steroid hormones and is expressed in both cervix and epididymis.

SCGB2A1 - Cervix
SCGB2A1 - Epididymis

Cervix function

The endocervix produces cervical mucus every day, with a peak around ovulation. The mucus viscosity changes during the menstrual cycle allowing it to act as either a barrier or a transport medium for sperm. The viscosity is determined by the hormones estrogen and progesterone. During ovulation, when estrogen levels are high, the mucus is thin, allowing sperm to enter the uterus. At other times in the cycle, the effect of progesterone makes the mucus thick, creating a barrier to sperm. The mucus also prevents pathogens from reaching the uterine body.

During pregnancy, a cervical mucus plug is formed to protect against pathogens and prevent the leakage of fluids. The cervix also supports the fetal head as it descends in preparation for birth. The support gives way during labor when the uterus begins to contract. At this time the cervix, which previously was closed off, degrades its mucus plug and dilates to approximately 10 cm through the softening of the cervical tissue which increases the elasticity of the cervical stroma and makes it possible for the infant to pass throug

Cervix histology

The cervix measures around 2–3 centimeters in length. It is part of the female reproductive system situated between the vagina and the uterine body. The cervix is composed of fibrous, muscular and elastic tissue lined with columnar and squamous epithelium. The lower part of the cervix is known as the ectocervix and is composed of squamous epithelial cells, resembling the vaginal epithelium. The cervical canal, connecting the vagina with the uterine body, is lined with columnar epithelial cells and contains underlying glandular structures. This is known as the endocervix. The mucosa covering the ectocervix is known as the exocervix. The junction between the endocervix and the ectocervix is called the squamocolumnar junction. This junction is where most cervical cancers arise. Human Papilloma Virus (HPV) is the cause of nearly all cervical cancers.

The histology of human cervix, uterine including detailed images and information about the different cell types can be viewed in the Protein Atlas Histology Dictionary.

Background

Here, the protein-coding genes expressed in cervix are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in cervix.

Transcript profiling was based on a combination of two transcriptomics datasets (HPA and GTEx), corresponding to a total of 14590 samples from 54 different human normal tissue types. The final consensus normalized expression (nTPM) value for each tissue type was used for the classification of all genes according to the tissue-specific expression into two different categories, based on specificity or distribution.

Relevant links and publications

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu NY et al., Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res. (2015)
PubMed: 26117540 DOI: 10.1093/nar/gkv608

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

Histology dictionary - the cervix, uterine