The cervix-specific proteome
The cervix measures around 2–3 centimeters in length. It is a tubular pathway between the vagina and the uterine body with regulated passage. The cervical glands produce mucus that changes during the menstrual cycle to act as a barrier or a transport medium to sperms dependent on the viscosity of the mucus. The mucin also prevents bacteria from reaching the uterine cavity. During pregnancy a cervical mucus plug is formed that seals the cervical canal. At time of labour, the normally narrow cervix is dilated to approximately 10 cm, by softening and increasing the elasticity in the cervical stroma. Transcriptome analysis shows that 76% (n=14959) of all human proteins (n=19670) are expressed in the cervix and 131 of these genes show an elevated expression in cervix compared to other tissue types.
The cervix transcriptome
Transcriptome analysis of the cervix can be visualized with regard to 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:
Distribution, on the other hand, visualizes how many genes that have, or do not have, detectable levels (NX≥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:
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 (NX≥1) in cervix as well as in all other tissues.
As shown in Figure 1, 131 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. 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.
Proteins related to expression in squamous epithelial cells in cervix
Examples of proteins with elevated expression in the squamous epithelium of cervix (ectocervix) include SERPINB3, which may act as a papain-like cysteine protease inhibitor, keratin 6a, KRT6A, a fibrous 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.
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.
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.
Gene expression shared between the cervix and other tissues
There are 27 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.
In order to illustrate the relation of cervix tissue to other tissue types, a network plot was generated, displaying the number of genes with 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 3 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 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 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.
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.
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 labour 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 through.
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) are the cause of nearly all cervical cancers.
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.
Relevant links and publications
Uhlén M et al, 2015. Tissue-based map of the human proteome. Science