# ZSWIM9

Zinc finger SWIM-type containing 9 is a protein encoded in humans by the ZSWIM9 gene. It is a member of zinc finger SWIM-type family. This gene is expressed in embryonic development and predicted to act in cell differentiation.

## Gene

The ZSWIM9 gene is located on the plus strand at 19q13.33 from 48,170,680 to 48,197,620 spanning 26,941 base pairs. Also known as C19orf68, this gene has orthologs in placental mammals, marsupials, reptiles (turtles), birds (flightless birds), and amphibians. ZSWIM9 has 4 exons, with variation between isoforms.

## mRNA and transcriptional variants
### Transcripts

ZSWIM9 has a total of six transcriptional variants with isoform 1 being the most complete and understood. All isoforms contain a conserved domain, FAR1, except X3 and X5, as well as the SWIM-type domain.
Transcript variants of ZSWIM9 :
| Transcript Variant | Accession number | mRNA length (nucelotides) | Protein length (amino acids) | Molecular weight (kDa) |
| 1 | NM_199341.4 | 3600 | 920 | 101.7 |
| X1 | XM_006723204.4 | 3914 | 947 | 104.6 |
| X2 | XM_005259449.4 | 4281 | 933 | 103.2 |
| X3 | XM_006723205.3 | 3596 | 920 | 101.6 |
| X4 | XM_011526936.3 | 3624 | 848 | 93.1 |
| X5 | XM_047438788.1 | 3130 | 720 | 80.0 |
Exons present in each isoform of ZSWIM9 :
| Isoform | Exon 1 | Exon 2 | Exon 3 | Exon 4 |
| 1 | ✓ | ✓ | ✓ | ✓ |
| X1 | ✓ | ✓ | ✓ | ✓ |
| X2 | ✓ | ✓ | ✓ | ✓ |
| X3 | ✓ | ✓ | ✓ | ✓ |
| X4 | x | x | ✓ | ✓ |
| X5 | x | x | x | ✓ |

## Protein

The human ZSWIM9 protein is 920 amino acids long with a molecular weight of 101.7 kDA and a theoretical isoelectric point of 8.51.

### Composition

The human ZSWIM9 protein along with orthologs has higher than normal amounts of arginine, specifically around amino acids 379-421. Arginine has been seen to play a crucial role in genome stability and typically associated with interactions with nucleic acids, specific cellular localization (nucleus), or involvement in structural or enzymatic roles. The high concentration of arginine residues influences the protein's charge, binding properties, and potential regulatory functions. Arginine-rich proteins can play crucial roles in cell differentiation during embryonic development due to their involvement in processes that regulate gene expression, chromatin remodeling, and signaling pathways.

### Conserved domains/motifs

ZSWIM9 contains a zinc finger SWIM-type profile, a pattern recognized in human protein ZSWIM9 and its orthologs that represent a shared zinc-binding motif. The acronym "SWIM" stands for SWI2/SNF2 and MuDR and detects conserved cysteine- and histidine-rich regions involved in zinc coordination, which facilitates protein-DNA or protein-protein interactions.
There is a conserved FAR1 DNA-binding domain from amino acids 97-128. This indicates that ZSWIM9, a member of the FRS family, shares a domain architecture with mutator-like transposases, including an N-terminal C2H2 zinc finger domain, a central transposase-like domain, and a C-terminal SWIM motif. This structure, coupled with its FAR1-like DNA-binding domain, suggests ZSWIM9 functions as a transcriptional regulator, potentially co-opted from transposases to play roles in gene expression, DNA repair, or transposon splicing.
There is a family of unknown function (DUF5575) from amino acids 12-320.

## Regulation
### Gene level regulation

Located in the nucleoplasm, ZSWIM9 in humans is ubiquitously expressed in medium abundance in the brain (fetal brain, and cerebellum), fat, and kidneys. Ubiquitously expressed, with some variability, in low abundance in early developed fetal hearts and fetal lungs.
While ZSWIM9 is expresses in low levels among fetal hearts, it has been predicted that there is a higher expression in earlier developed embryoid stem cells and embryoid bodies with beating cardiomyocytes, then a decreased level of expression later on in development such as in mature cardiomyocytes from fetal hearts. This suggests ZSWIM9 might play a role in early differentiation stages and cellular commitment processes.
Additionally, higher expression of ZSWIM9 was seen in myotonic dystrophy type 2, which is muscle dysfunction in numerous muscle types including cardiac, compared to a control from DM2 vastus lateralis muscle tissue. Higher expression suggests that ZSWIM9 may have a role in the muscle’s response to chronic disease-related stress, regeneration process, or damage repair. This pattern of expression may reflect ZSWIM9’s involvement in cellular pathways that become more active or dysregulated in the disease state.

### Protein level regulation

The human ZSWIM9 protein is predicted to be primarily localized in the nucleus and cytoplasm, however, it has also been visualized via immunofluorescence in the nucleoplasm. It was also predicted ZSWIM9 has nuclear export signals, which direct proteins from the nucleus to the cytoplasm. The presence of an NES indicates the protein may shuttle between the nucleus and cytoplasm, depending on cellular conditions or specific signals (e.g., stress, phosphorylation).
Phosphorylation

## Interacting proteins

ZSWIM9 was found to primarily interact with proteins involved with DNA maintenance in the nucleus, cytoplasm, and nucleoplasm.
ZSWIM9 interacting proteins :
| Protein | Detection method | Subcellular localization | Function |
| Chromobox protein homolog 1 | Tandem affinity purification | Nucleus, nucleoplasm, chromosome, cytoskeleton | Component of heterochromatin. Recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression. Interaction with lamin B receptor (LBR) can contribute to the association of the heterochromatin with the inner nuclear membrane. |
| BMI1 (Polycomb complex protein) | Co-immunoprecipitation | Nucleus, nucleoplasm, chromosome, cytosol | Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. |
| CBX3 (Chromobox 3) | Co-immunoprecipitation | Nucleus, nuclear envelope, nucleoplasm, chromosome, cytoskeleton | Seems to be involved in transcriptional silencing in heterochromatin-like complexes. Recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression. May contribute to the association of the heterochromatin with the inner nuclear membrane through its interaction with the lamin B receptor (LBR). |
| FHL3 (Human four-and-a-half LIM-only protein 3) | Co-immunoprecipitation | Nucleus, cytoskeleton | Recruited by SOX15 to FOXK1 promoters where it acts as a transcriptional coactivator of FOXK1. |
Histone 3 (H3) is an arginine-rich histone and is linked active chromatin structures and gene activation.
Hox genes are a group of related genes that play a critical role in the development and organization of an organism's body plan during embryonic development. This is indicative of ZSWIM9 protein function.
SOX15 binds to the DNA consensus sequence 5'-AACAATG-3' and can function as both an activator and repressor. It synergistically interacts with POU5F1 (OCT3/4) at gene promoters and activates the FOXK1 promoter by recruiting FHL3, promoting myoblast proliferation. Additionally, it inhibits myoblast differentiation by repressing muscle-specific genes like MYOD and MYOG.

## Evolution
### Paralogs

ZSWIM9 has paralogs in ZSWIM1-8 as it is a part of the zinc finger SWIM-type gene family and the SWIM domain is conserved throughout. However, it's two closely conserved paralogs are ZSWIM1 and ZSWIM3.

### Orthologs

Orthologs of ZSWIM9 were found in placental mammals, marsupials, reptiles, birds, and amphibians. ZSWIM9 is found in reptiles, but only in turtles and in birds, but only in flightless birds. This could indicate a key point of divergence or a result of ZSWIM9 protein function.
Selected Orthologs of ZSWIM9 :
| Organism type | Species name | Common name | Taxonomic group | Date of divergence (MYA) | % Identity | % Similarity | AC# | Protein length |
| Placental | Homo sapiens | Human | Primate | 0 | 100 | 100 | NP_955373 | 920 |
| Placental | Oryctolagus cuniculus | Rabbit | Lagomorpha | 87 | 69 | 73 | XP_051693391 | 913 |
| Placental | Mus musculus | House mouse | Rodentia | 87 | 67.9 | 74.2 | NP_796286.2 | 849 |
| Placental | Camelus ferus | Wild Bactrian camel | Artiodactyla | 94 | 85.4 | 89.2 | XP_032341552.1 | 923 |
| Placental | Vulpes lagopus | Arctic fox | Carnivora | 94 | 84.8 | 69.6 | XP_041600653 | 915 |
| Placental | Equus przewalskii | Przewalski's horse | Perissodactyla | 94 | 47.8 | 51.4 | XP_008525788 | 611 |
| Marsupial | Trichosurus vulpecula | Common brushtail possum | Diprotodotia | 160 | 80.2 | 48.1 | XP_036599503.1 | 717 |
| Marsupial | Vombatus ursinus | Common wombat | Diprotodotia | 160 | 75.6 | 65.2 | XP_027715069.1 | 966 |
| Marsupial | Antechinus flavipes | Yellow-footed antechinus | Dasyuromorphia | 160 | 74.4 | 56.2 | XP_051845809 | 898 |
| Marsupial | Sarcophilus harrisii | Tasmanian devil | Dasyuromorphia | 160 | 74.3 | 62.7 | XP_031817585 | 1030 |
| Reptile | Dermochelys coriacea | Leatherback sea turtle | Testudines | 319 | 61.9 | 43.2 | XP_043357605.1 | 538 |
| Reptile | Emydura macquarii | Murrey river turtle | Testudines | 319 | 61.8 | 43.6 | XP_067413334.1 | 538 |
| Bird | Rhea pennata | Darwin's rhea | Rheiformes | 319 | 44.2 | 33.5 | XP_062449005.1 | 535 |
| Bird | Apteryx rowi | Okarito kiwi | Apterygiformes | 319 | 43.3 | 33.4 | XP_025945372.1 | 535 |
| Bird | Dromaius novaehollandiae | Emu | Palaeognathae | 319 | 43.1 | 33.5 | XP_025976311.1 | 535 |
| Amphibian | Rhinatrema bivittatum | Two-lined caecilian | Gymnophiona | 352 | 51.9 | 39.7 | XP_029440252.1 | 548 |
| Amphibian | Geotrypetes seraphini | Gaboon caecilian | Gymnophiona | 352 | 50.1 | 38.5 | XP_038816602.1 | 548 |
| Amphibian | Microcaecilia unicolor | Tiny cayenne caecilian | Gymnophiona | 352 | 50 | 38.5 | XP_030053572.1 | 544 |
| Amphibian | Ascaphus truei | Coastal tailed frog | Anura | 352 | 49.3 | 38.3 | MEE6483311.1 | 536 |
| Amphibian | Ambystoma mexicanum | Axolotl | Urodela | 352 | 46.9 | 36.6 | XP_069493689.1 | 544 |
| Amphibian | Pleurodeles waltl | Iberian ribbed newt | Urodela | 352 | 45.8 | 34.9 | XP_069056600.1 | 580 |

## Function

Zinc-finger proteins contain a short finger-like structural motif stabilized by zinc-ions which are involved in critical biological processes including cell differentiation and embryonic development. ZSWIM9, however, is classified by the SWIM domain, characterized by a CxCxnCxH molecular structure. The SWIM domain is predicted to have DNA-binding and protein-protein interaction functions.

## Clinical significance

A couple of single nucleotide polymorphisms (SNPs) were identified as clinically significant and associated with ZSWIM9. One study associate a SNP in ZSWIM9 with acute Graft versus Host Disease (aGvHD) which affects patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). This condition is triggered by the damage to normal tissue caused by pre-transplant conditioning regimens, with DNA-repair mechanisms potentially playing a key role in mitigating this damage. This could be associated with proteins involved in cell differentiation through several mechanisms related to DNA repair, gene expression regulation, and cellular responses to stress or injury.
An additional SNP was identified with ZSWIM9 and associated with body height.