CDY1

Last updated
CDY1
Protein CDY1 PDB 2fbm.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases CDY1 , CDY, CDY1A, chromodomain protein, Y-linked, 1, chromodomain Y-linked 1
External IDs OMIM: 400016; HomoloGene: 36165; GeneCards: CDY1; OMA:CDY1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9085

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Ensembl

ENSG00000172288

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UniProt

Q9Y6F8

n/a

RefSeq (mRNA)

NM_004680
NM_170723

n/a

RefSeq (protein)

NP_004671
NP_733841

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Location (UCSC) Chr Y: 25.62 – 25.62 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Overview

Testis-specific Chromodomain protein Y 1 is a protein that in humans is encoded by the CDY1 gene. [3] [4]

Contents

This gene encodes a protein containing a chromodomain and a histone acetyltransferase catalytic domain. Chromodomain proteins are components of heterochromatin-like complexes and can act as gene repressors. This protein is localized to the nucleus of late spermatids where histone hyperacetylation takes place. Histone hyperacetylation is thought to facilitate the transition in which protamines replace histones as the major DNA-packaging protein. The human chromosome Y has two identical copies of this gene within a palindromic region; this record represents the more telomeric copy. Chromosome Y also contains a pair of closely related genes in another more telomeric palindrome as well as several related pseudogenes. Two protein isoforms are encoded by transcript variants of this gene. Additional transcript variants have been described, but their full-length nature has not been determined. [4] The gene is thought to be related to high-altitude adaptation in humans. [5]

It is a largely studied gene located on the long arm of the human Y chromosome (Yq11.23) within the Azoospermia Factor c (AZFc) region. [6] [7] [8] The clinical significance of CDY1 stems from its presence in the AZFc region, where recurrent large-scale deletions are recognized as the single most common molecular cause of severe male infertility, including non-obstructive azoospermia (NOA) and severe oligozoospermia. [9] [10] [11]

The initial identification of CDY1 was an outcome of intensive research focused on mapping the male-specific region of the Y (MSY) chromosome and pinpointing genes essential for fertility. [12] Early genetic analyses of men with severe spermatogenic failure revealed recurrent microdeletions spanning Yq11, leading to the designation of the Azoospermia Factor (AZF) loci (AZFa, AZFb, and AZFc). [7] CDY1 was cloned and characterized as part of the AZFc complement, where it was distinguished by its unique protein domains. [6] Notably, CDY1 possesses both a chromodomain and a C-terminal region that functions as an atypical histone acetyltransferase (HAT), an enzymatic activity fundamental to its role in chromatin modification. [6]

The discovery of CDY1 and its associated gene family profoundly advanced the understanding of Y-chromosome function. It demonstrated that the Y chromosome is not merely a collection of degenerated genes but harbors specialized gene families that have undergone adaptive amplification and specialization for the sole purpose of ensuring male reproductive fitness. [13] [14] The highly restricted expression pattern of CDY1—being almost exclusively expressed in the testis—solidified its role as a key player in the specialized cellular processes of germ cell development. [15]

Gene structure, family, and evolutionary origin

The CDY gene family epitomizes the structural and evolutionary dynamics of the Y chromosome’s male-specific region, characterized by high sequence repetition, large palindromic structures, and a retropositional origin. [13] [14] [7] [11] The family is extensive, encompassing two main functional genes, CDY1 and CDY2 (including CDY2A and CDY2B), along with several related pseudogenes (CDYP) scattered across the Y chromosome and autosomes. [11]

Retropositional origin

The evolutionary origin of the CDY gene family is a classic example of retroposition. [13] This process occurred when a messenger RNA (mRNA) transcript of an autosomal parent gene, Chromodomain Protein, Y-Like (CDYL), was reverse-transcribed into DNA and subsequently inserted into the Y chromosome. [13]

The autosomal CDYL gene, located on chromosome 6 (6p22), is expressed ubiquitously across somatic tissues and is an intron-containing gene. [13] In contrast, the retroposed CDY genes on the Y chromosome lack introns indicative of their mRNA-derived origin. [13] The retropositional event led to the creation of a new gene family that retained the core functional architecture of the parent gene but gained a novel, testis-specific expression pattern due to its insertion into the specialized germline regulatory environment of the Y chromosome. [13] This divergence in expression profiles represents an adaptation where the functional domains of a ubiquitous chromatin regulator were co-opted and amplified to serve the unique requirements of mammalian spermatogenesis. This event is estimated to have occurred within the primate lineage, subsequent to the divergence of Old World monkeys. [13]

Palindromic architecture and copy number

The CDY1 gene is located in the most common deletion interval, AZFc, which is characterized by the presence of vast palindromic structures. [7] The human genome contains two identical copies of the CDY1 coding sequence, referred to as CDY1A and CDY1B. [11] These two copies are situated within the large palindrome P1/P5 on Yq11.23. [7]

This complex architecture serves a biological purpose in genomic instability. The high sequence homology between the inverted repeats renders the AZFc region inherently unstable and prone to non-allelic homologous recombination (NAHR) errors during meiosis. [7] These errors are the mechanism driving the frequent AZFc microdeletions, where the homologous segments recombine incorrectly, excising the intervening gene copies, including CDY1A and CDY1B. [7] [16] The size and position of the recombining segments determine the type of deletion, with the complete AZFc deletion leading to the loss of all CDY1 copies. [11]

The related CDY2 gene family resides in a different palindromic arm, contributing further to the overall complexity and dosage of the chromodomain/HAT-containing proteins on the Y chromosome. [11] The coordinated evolution in copy number and sequence within the entire CDY family suggests strong selective pressure to maintain a precise functional dosage of these specialized chromatin modifiers. [11] [17]

Transcript variants and isoforms

Analysis of the CDY1 gene has demonstrated the existence of multiple transcript variants arising from alternative splicing. [15] [17] These variants encode at least two major protein isoforms, though the complete functional characterization of all possible full-length transcripts remains an ongoing area of research. [15] Differences in isoforms may affect the protein’s stability, its exact subcellular localization, or its affinity for different histone substrates, potentially introducing subtle variations in regulation or function throughout the stages of spermatogenesis. [17]

Protein structure and molecular function

The CDY1 protein is a bifunctional chromatin regulator, structurally defined by two distinct domains that coordinate its targeting and enzymatic activity. [6] The combined actions of these domains are specifically adapted to drive the massive nuclear restructuring that takes place in post-meiotic germ cells.

Dual functional domains

1. The chromodomain

The N-terminal chromodomain is an evolutionarily ancient protein module found in numerous chromatin-associated factors. [18] Its conserved structure allows it to function as a methylated histone binding module. [18] For CDY1, the chromodomain is essential for recognizing and binding to specific epigenetic marks. In the context of spermiogenesis, the chromodomain of CDY1 acts as a targeting moiety. [6] By binding to existing methylated marks, the chromodomain ensures that the enzymatic activity of the protein—the histone acetyltransferase domain—is recruited to the correct segments of the spermatid chromatin at the precise moment in development. [6] This site-specific recruitment is critical for initiating the cascade of modifications necessary for chromatin decompaction.

2. Histone acetyltransferase activity

The C-terminal domain of CDY1 exhibits intrinsic histone acetyltransferase (HAT) activity. [6] HATs are enzymes that transfer an acetyl group from acetyl-Coenzyme A (acetyl-CoA) onto the lysine residues on histone tails, a process that neutralizes the positive charge of the histone tail. [6] This neutralization weakens the electrostatic interaction between the histones and the negatively charged DNA molecule, effectively loosening the chromatin structure.

In most cells, HAT activity is associated with transcriptionally active (euchromatin) regions. CDY1 functions by performing a global hyperacetylation of histones, particularly Histone H4 and Histone H2A, in the post-meiotic spermatid. [6] This massive acetylation does not lead to general transcription, but rather serves as the necessary destabilizing force for nucleosome structure. [6] The hyperacetylated histones are then recognized and replaced by transition proteins, which are themselves transiently replaced by highly compacting proteins called protamines. [6] This complete exchange of histones for protamines is the defining feature of spermiogenesis, leading to the exceptionally small and dense nucleus of the mature sperm cell, protecting the paternal DNA. [6] CDY1, therefore, functions as a critical initiator of this fundamental chromatin remodeling cascade. [6]

Expression pattern and cellular localization

The function of CDY1 is intrinsically linked to its highly specific expression profile, demonstrating precise temporal and spatial regulation within the male reproductive system. [15] [6] [17]

Testis-specific expression

The CDY1 gene exhibits a pattern of expression that is nearly exclusive to the testis in adults. [15] Analysis of mRNA and protein levels across various human tissues confirms that expression is minimal or absent in somatic cells, indicating a tightly controlled, lineage-specific role. [15] [17] This specificity is consistent with the evolutionary origin of CDY1 from a ubiquitous autosomal gene (CDYL) that was retroposed and subsequently adapted to the male germline. [13]

Subcellular location

Consistent with its role as a chromatin modifier, the CDY1 protein is localized within the nucleus of developing germ cells. [6] Specifically, immunofluorescence studies show the protein concentrated in the nuclear chromatin of late-stage spermatids. [6] This nuclear presence is a prerequisite for its HAT activity—it must be physically present to acetylate the histone tails, destabilizing the nucleosome structure in preparation for protamine exchange. [6] Its localization pattern highlights the irreversible commitment of these cells to DNA compaction and terminal differentiation.

Stage-specific timing

The timing of CDY1 expression within the stages of spermatogenesis is highly specific and correlates directly with its required functional window. [6] [19] CDY1 transcripts are first detected in spermatocytes during the late-phase, where round spermatids are experiencing nuclear elongation. [6] [19] In the third and final stage, expression levels significantly increase and peak in post-meiotic cells, specifically elongating spermatids. [15] [6]

This temporal control is biologically crucial. The expression profile ensures that the CDY1 protein is synthesized and active at the precise time when the cell has completed meiosis and is ready to commence the intricate morphological and nuclear differentiation phase of spermiogenesis. [6] The presence of CDY1 mRNA thus serves as a reliable biological marker for the successful transition into and execution of the post-meiotic stage of sperm development. [9] [19]

Clinical significance and pathology in male infertility

The most pressing clinical relevance of the CDY1 gene is its association with male infertility, particularly due to its location within the deletion-prone AZFc region. [10] [9]

AZFc deletions: a major cause of azoospermia

The AZFc region houses gene families considered essential for quantitative and qualitative sperm production, including DAZ and CDY1. [7] AZFc deletions are the most frequently observed structural abnormality of the Y chromosome in infertile men. [10] [11]

Patients who have a complete AZFc deletion lose all copies of the CDY1 gene (both CDY1A and CDY1B), as well as all copies of the DAZ gene [7] . The resulting clinical phenotype is highly variable, ranging from non-obstructive azoospermia (NOA)—a complete absence of sperm in the ejaculate—to severe oligozoospermia (sperm concentration below 5 million/mL). [9] [10] The most severe forms of azoospermia linked to AZFc deletion often present as maturation arrest or hypospermatogenesis, reflecting the profound deficit in germ cell differentiation caused by the loss of essential genes like CDY1. [9]

CDY1 as a prognostic marker in testicular sperm extraction

In the clinical management of male infertility, particularly NOA, the ability to predict the success of surgical sperm retrieval via Testicular Sperm Extraction (TESE) is paramount. [9] [19] Successful TESE depends on finding focal areas of complete spermatogenesis within the testis tissue, which are often not reflected in the seminal fluid. [19]

Molecular analysis of testicular biopsy samples for the presence of specific gene transcripts has been developed as a prognostic tool. [9] [17] Studies comparing the expression of various Y-linked genes have demonstrated that the detection of CDY1 mRNA transcripts is a highly reliable indicator of advanced germ cell differentiation. [17] [19] The expression of CDY1 has been shown to correlate more strongly with the presence of mature spermatids (and thus a higher chance of successful TESE) than other commonly screened genes, such as DAZ or BPY2. [17]

The rationale for this correlation is CDY1's unique stage-specificity: its function as a HAT is crucial for the very last steps of nuclear differentiation that lead directly to the formation of haploid spermatozoa. [6] [19] The presence of CDY1 transcript in a biopsy therefore implies that the seminiferous tubule is functionally capable of completing the full differentiation pathway. [9] [19] This molecular evidence provides valuable guidance for clinicians considering TESE, helping to refine patient selection and manage expectations. [9]

Comparative genomics and evolutionary dynamics

The study of CDY1 and its gene family across different species provides insight into the powerful selective pressures that have shaped the genes responsible for male germline function. [11] [20]

Evolution of the CDY gene family in primates

The CDY gene family displays a pattern of coordinated evolution across the primate lineage. [11] This means that when a change in copy number or sequence occurred in one member (e.g., CDY1), it was often mirrored or compensated for by changes in other members (CDY2, CDYL), maintaining an overall functional equilibrium or optimal dosage for spermatogenesis. [11] This phenomenon strongly implies that the total functional output of the CDY-like proteins is under strict evolutionary constraint, favoring reproductive success. [11] Research on the cynomolgus monkey, for instance, revealed the existence of a conserved cynCDY orthologue that maintains the dual chromodomain and HAT activity, confirming that the basic functional architecture of the protein is ancient and essential for primate germline development. [20]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000172288 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ Lahn BT, Page DC (October 1997). "Functional coherence of the human Y chromosome". Science. 278 (5338): 675–680. Bibcode:1997Sci...278..675L. doi:10.1126/science.278.5338.675. PMID   9381176.
  4. 1 2 "Entrez Gene: CDY1 chromodomain protein, Y-linked, 1".
  5. ↑ Zhang YB, Li X, Zhang F, Wang DM, Yu J (2012). "A preliminary study of copy number variation in Tibetans". PLOS ONE. 7 (7) e41768. Bibcode:2012PLoSO...741768Z. doi: 10.1371/journal.pone.0041768 . PMC   3402393 . PMID   22844521.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Lahn, Bruce T.; Tang, Zhao Lan; Zhou, Jianxin; Barndt, Robert J.; Parvinen, Martti; Allis, C. David; Page, David C. (2002-06-25). "Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis". Proceedings of the National Academy of Sciences of the United States of America. 99 (13): 8707–8712. doi:10.1073/pnas.082248899. ISSN   0027-8424. PMC   124363 . PMID   12072557.
  7. 1 2 3 4 5 6 7 8 9 Skaletsky, Helen; Kuroda-Kawaguchi, Tomoko; Minx, Patrick J.; Cordum, Holland S.; Hillier, LaDeana; Brown, Laura G.; Repping, Sjoerd; Pyntikova, Tatyana; Ali, Johar; Bieri, Tamberlyn; Chinwalla, Asif; Delehaunty, Andrew; Delehaunty, Kim; Du, Hui; Fewell, Ginger (2003-06-19). "The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes". Nature. 423 (6942): 825–837. doi:10.1038/nature01722. ISSN   0028-0836.
  8. ↑ UCSC Genome Browser. "Human Genome Assembly hg38, position chrY:25622117-25624902".
  9. 1 2 3 4 5 6 7 8 9 Kleiman, Sandra E; Lagziel, Ayala; Yogev, Leah; Botchan, Amnon; Paz, Gedalia; Yavetz, Haim (2001-01-01). "Expression of CDY1 may identify complete spermatogenesis". Fertility and Sterility. 75 (1): 166–173. doi:10.1016/S0015-0282(00)01639-3. ISSN   0015-0282.
  10. 1 2 3 4 Ferlin, A.; Moro, E.; Rossi, A.; Foresta, C. (2001-02-01). "CDY 1 analysis in infertile patients with DAZ deletions". Journal of Endocrinological Investigation. 24 (2): RC4 –RC6. doi:10.1007/BF03343814. ISSN   1720-8386.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 Dorus, S. (2003-07-15). "The CDY-related gene family: coordinated evolution in copy number, expression profile and protein sequence". Human Molecular Genetics. 12 (14): 1643–1650. doi:10.1093/hmg/ddg185. ISSN   1460-2083.
  12. ↑ Yen, Pauline H. (1998-11-15). "A Long-Range Restriction Map of Deletion Interval 6 of the Human Y Chromosome: A Region Frequently Deleted in Azoospermic Males". Genomics. 54 (1): 5–12. doi:10.1006/geno.1998.5526. ISSN   0888-7543.
  13. 1 2 3 4 5 6 7 8 9 Lahn, Bruce T; Page, David C (April 1, 1999). "Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome". Nature Genetics. 21: 429–433.
  14. 1 2 Mammalian Gene Collection (MGC) Program Team (2002-12-24). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC   139241 . PMID   12477932.
  15. 1 2 3 4 5 6 7 Saut, N. (2000-09-01). "The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility". Molecular Human Reproduction. 6 (9): 789–793. doi:10.1093/molehr/6.9.789.
  16. ↑ Kamp, C.; Hirschmann, P.; Voss, H.; Huellen, K.; Vogt, P. H. (2000-10-12). "Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events". Human Molecular Genetics. 9 (17): 2563–2572. doi:10.1093/hmg/9.17.2563. ISSN   0964-6906. PMID   11030762.
  17. 1 2 3 4 5 6 7 8 Kleiman, Sandra E.; Yogev, Leah; Hauser, Ron; Botchan, Amnon; Bar-Shira Maymon, Batia; Schreiber, Letizia; Paz, Gedalia; Yavetz, Haim (3 September 2003). "Members of the CDY family have different expression patterns: CDY1 transcripts have the best correlation with complete spermatogenesis". Human Genetics. 113: 486–492 – via Springer Nature Link.
  18. 1 2 Jones, David O.; Cowell, Ian G.; Singh, Prim B. (2000). "Mammalian chromodomain proteins: their role in genome organisation and expression". BioEssays. 22 (2): 124–137. doi:10.1002/(SICI)1521-1878(200002)22:2<124::AID-BIES4>3.0.CO;2-E. ISSN   1521-1878.
  19. 1 2 3 4 5 6 7 8 Schrader, M.; Müller, M.; Schulze, W.; Heicappell, R.; Krause, H.; Straub, B.; Miller, K. (January 2002). "Quantification of the expression level of the gene encoding the catalytic subunit of telomerase in testicular tissue specimens predicts successful sperm recovery". Human Reproduction (Oxford, England). 17 (1): 150–156. doi:10.1093/humrep/17.1.150. ISSN   0268-1161. PMID   11756380.
  20. 1 2 Kostova, E. (2002-08-01). "Identification and characterization of the cynomolgus monkey chromodomain gene cynCDY, an orthologue of the human CDY gene family". Molecular Human Reproduction. 8 (8): 702–709. doi:10.1093/molehr/8.8.702.


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