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UniProt release 2014_02

Published February 19, 2014

Headline

Epigenetics in the spotlight

In its active form, folate, commonly known as vitamin B9, is a methyl carrier, essential for the biosynthesis of methionine and nucleic acids, most notably thymine, but also purine bases. Methionine synthesis involves first the activation of methionine synthase (MTR) by methionine synthase reductase (MTRR) and then the MTR-catalyzed conversion of homocysteine into methionine concomitant with conversion of 5-methyltetrahydrofolate into tetrahydrofolate. Methionine can be further modified into S-adenosyl methionine which serves as a methyl donor in the biosynthesis of cysteine, carnitine, taurine, lecithin, and phospholipids, among others.

Folate deficiency can result in many health problems, the most notable one being neural tube defects in developing embryos, but the molecular mechanism linking folate metabolism to development remains poorly understood. This is what prompted Padmanabhan et al. to create an animal model to study the impact of abnormal folate metabolism. These authors produced a mouse that contained a gene trap vector inserted in Mtrr gene intron 9. Wild-type Mtrr mRNA was still produced in spite of the insertion, but at lower levels, and folate metabolism was impaired.

When mid-gestation embryos from heterozygous intercrosses were analyzed, it appeared that about half of them displayed developmental defects typical of folate deficiency, ranging from developmental delay to neural tube and heart defects. Surprisingly, wild-type embryos were affected to a similar extent as embryos bearing the mutated gene. Inheritance of the phenotype was not dependent upon the parental genotype, but instead upon that of the maternal grandparents. In other words, Mtrr mutations in either maternal grandparent disrupted the development of their grandchildren, even when the parents and the conceptus were wild-type. These congenital abnormalities persisted in wild-type progeny in generations 4 and 5 of Mtrr mutant maternal ancestors.

What could be the mechanism of this peculiar mode of inheritance? The answer is not yet definite. Because folate plays a key role in one-carbon metabolism, the authors investigated DNA methylation. As expected, global DNA hypomethylation was observed in livers, uteri and placentas. Imprinted loci (differentially methylated regions or DMRs) in wild-type placentas of mid-gestation embryos from heterozygous maternal grandparents were also analyzed. A large proportion of the DMRs assessed in placentas of severely affected embryos had CpG site methylation levels that were statistically different from unrelated wild-type C57BL/6 mice. Surprisingly however, the majority of these sites were hypermethylated and the associated genes down-regulated. There was a positive correlation between epigenetic instability and the severity of the phenotype. Hence, epigenetic instability leading to the misexpression of certain genes may be the cause of developmental phenotypes.

Epigenetic heredity has been reported for Kit and Sox9 genes. In this case, heredity was mediated by RNA, a mechanism rather unlikely for the Mtrr mutations described above. The RNA-mediated heredity observed for Kit and Sox9 required the presence of the tRNA-methyltransferase TRDMT1/DNMT2. Hence, for both phenomena, it seems that the common feature may be methylation, either at the DNA or RNA level.

While awaiting further exciting discoveries in the field of epigenetics, we have already updated MTRR entries with the current knowledge and made them available.

UniProtKB news

Change of the cross-references to PROSITE and HAMAP

The format of the cross-references to the PROSITE and HAMAP databases has been simplified in order to align it with the format of other InterPro member databases.

Text format

Changes for PROSITE:

The optional qualifiers "UNKNOWN", "FALSE_NEG" and "PARTIAL" have been removed. Only matches above the threshold were kept, i.e. cross-references with a "FALSE_NEG" or "PARTIAL" qualifier have been removed.

Examples:

A1RHR2:

Previous format:

DR   PROSITE; PS51257; PROKAR_LIPOPROTEIN; UNKNOWN_1.
DR   PROSITE; PS00922; TRANSGLYCOSYLASE; FALSE_NEG.

New format:

DR   PROSITE; PS51257; PROKAR_LIPOPROTEIN; 1.

O02781:

Previous format:

DR   PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; PARTIAL.
DR   PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.

New format:

DR   PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.

Changes for HAMAP:

The optional field that described the nature of signature hits ("atypical", "fused" or "atypical/fused") has been removed. Only matches above the threshold were kept, i.e. "atypical" and "atypical/fused" cross-references have been removed if their match score was below the threshold.

Example:

Q9K3D6:

Previous format:

DR   HAMAP; MF_00006; Arg_succ_lyase; 1; fused.
DR   HAMAP; MF_01105; N-acetyl_glu_synth; 1; atypical/fused.

New format:

DR   HAMAP; MF_00006; Arg_succ_lyase; 1.

XML format

Changes for PROSITE:

The optional values "UNKNOWN", "FALSE_NEG" and "PARTIAL" that were stored in a property of type match status have been removed, so that the match status value has become an integer. Only matches above the threshold were kept, i.e. "FALSE_NEG" and "PARTIAL" cross-references have been removed.

Examples:

A1RHR2:

Previous format:

<dbReference type="PROSITE" id="PS51257">
  <property type="entry name" value="PROKAR_LIPOPROTEIN"/>
  <property type="match status" value="UNKNOWN_1"/>
</dbReference>
<dbReference type="PROSITE" id="PS00922">
  <property type="entry name" value="TRANSGLYCOSYLASE"/>
  <property type="match status" value="FALSE_NEG"/>
</dbReference>

New format:

<dbReference type="PROSITE" id="PS51257">
  <property type="entry name" value="PROKAR_LIPOPROTEIN"/>
  <property type="match status" value="1"/>
</dbReference>

O02781:

Previous format:

<dbReference type="PROSITE" id="PS00237">
  <property type="entry name" value="G_PROTEIN_RECEP_F1_1"/>
  <property type="match status" value="PARTIAL"/>
</dbReference>
<dbReference type="PROSITE" id="PS50262">
  <property type="entry name" value="G_PROTEIN_RECEP_F1_2"/>
  <property type="match status" value="1"/>
</dbReference>

New format:

<dbReference type="PROSITE" id="PS50262">
  <property type="entry name" value="G_PROTEIN_RECEP_F1_2"/>
  <property type="match status" value="1"/>
</dbReference>

Changes for HAMAP:

The optional property of type flag that described the nature of signature hits ("atypical", "fused" or "atypical/fused") has been removed. Only matches above the threshold were kept, i.e. "atypical" and "atypical/fused" cross-references have been removed if their match score was below the threshold.

Example:

Q9K3D6:

Previous format:

<dbReference type="HAMAP" id="MF_00006">
  <property type="entry name" value="Arg_succ_lyase"/>
  <property type="flag" value="fused"/>
  <property type="match status" value="1"/>
</dbReference>
<dbReference type="HAMAP" id="MF_01105">
  <property type="entry name" value="N-acetyl_glu_synth"/>
  <property type="flag" value="atypical/fused"/>
  <property type="match status" value="1"/>
</dbReference>

New format:

<dbReference type="HAMAP" id="MF_00006">
  <property type="entry name" value="Arg_succ_lyase"/>
  <property type="match status" value="1"/>
</dbReference>

These changes did not affect the XSD, but may nevertheless require code changes.

Cross-references to TreeFam

Cross-references have been added to TreeFam, a database composed of phylogenetic trees inferred from animal genomes.

TreeFam is available at http://www.treefam.org.

The format of the explicit links is:

Resource abbreviation TreeFam
Resource identifier TreeFam unique identifier.

Example: Q8CFE6

Show all entries having a cross-reference to TreeFam.

Text format

Example: Q8CFE6

DR   TreeFam; TF328787; -.

XML format

Example: Q8CFE6

<dbReference type="TreeFam" id="TF328787"/>

Cross-references to BioGrid

Cross-references have been added to BioGrid, a public database that archives and disseminates genetic and protein interaction data from model organisms and humans.

BioGrid is available at http://thebiogrid.org.

The format of the explicit links is:

Resource abbreviation BioGrid
Resource identifier BioGrid unique identifier.
Optional information 1 Number of interactions.

Example: O46201

Show all entries having a cross-reference to BioGrid.

Text format

Example: O46201

DR   BioGrid; 69392; 1.

XML format

Example: O46201

<dbReference type="BioGrid" id="69392">
  <property type="interactions" value="1"/>
</dbReference>

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • N-methylglycine
  • N,N-dimethylglycine
  • N,N,N-trimethylglycine

Deleted term:

  • 3-hydroxyhistidine

UniRef news

Revision of the UniParc records used in the UniRef databases

We have stopped importing UniParc records that correspond to Ensembl proteomes sequences in the UniRef databases, as the relevant sequences are now part of UniProtKB. Previously, some sequences from Ensembl proteomes (e.g. from Human, Chicken, Cow) were missing from UniProtKB, but we have recently completed their import into UniProtKB (see FAQ) and thus no longer need to import them via UniParc. The UniRef databases will continue to include UniParc records from the RefSeq and PDB databases that are not in UniProtKB to ensure a complete sequence space coverage.