Biology Reference
In-Depth Information
5.2.1 Transcription factor families
Many mammalian transcription factors belong to families whose members bind
to very similar or identical DNA sequence motifs. Thus, there are at least eight
cAMP-reponsive transcription factors of the CREB/ATF family that bind to the
octanucleotide TGACGTCA (Hai
et al
., 1989). The evolutionary conservation of
DNA sequence recognition can be fairly dramatic as for example in the case of the
various members of the Brn-3 class of POU domain transcription factors found in
both mammals and nematodes (Gruber
et al
., 1997). On the other hand, some
transcription factor families possess members that exhibit a considerable degree
of divergence in terms of their DNA binding specificities. For example, at least
four members of the nuclear factor 1 (NF1) family recognize sequences contain-
ing the trinucleotide TGG (Gil
et al
., 1988) and at least eight members of the
mammalian
Ets
family bind to an 11 bp purine-rich motif containing a conserved
GGA core (Wang
et al
., 1992). The DNA binding specificity of different
Ets
fam-
ily members is determined by the nucleotides at the 3
end of the
Ets
-binding site
(Wang
et al
., 1992).
The evolutionary subdivisions of transcription factor families as revealed by
phylogenetic analysis may be paralleled by functional subdivisions (Elsen
et al
.,
1995). If function is conserved within (although not between) subfamilies, then
the functions of novel transcription factors may be to some extent predictable by
comparison with other members of the same subfamily. One example of this is
provided by the high mobility group (HMG) protein superfamily of DNA-bind-
ing proteins. These proteins possess one or more copies of an 80 amino acid
domain termed the HMG box and have an evolutionary history that dates back
1000 Myrs (Laudet
et al
., 1993). The HMG superfamily may be divided into two
sub-families (i) the TCF/SOX family which comprises transcription factor pro-
teins that contain a single sequence-specific HMG box and (ii) the UBF/HMG
family of chromatin structure regulatory proteins which possess multiple HMG
boxes that exhibit little if any sequence specificity. Representatives of the first
family in the human genome include the chromosomally dispersed SRY-related
HMG-box (SOX) genes (
SOX1
, 13q34;
SOX2
, 3q26-q27;
SOX3
, Xq26-q27;
SOX4
, 6p23;
SOX5
, 12p12;
SOX9
, 17q23;
SOX10
, 22q13;
SOX11
, 2p25;
SOX20
,
17p13;
SOX22
, 20p13; Wegner 1999), the lymphoid enhancer-binding factor 1
(
LEF1
; 4q23-q25) and the hepatocyte nuclear factor 1
(
TCF1
; 12q24) genes.
Human representatives of the second family include the high mobility group
(non-histone chromosomal) protein genes,
HMG1
(13q12),
HMG2
(4q31),
HMG4
(Xq28),
HMG14
(21q22) and
HMG17
(1p35-p36) and upstream binding
transcription factor (
UBTF
; 17q21). The diversity of function exhibited by mem-
bers of the HMG superfamily is a result of the action of a number of different evo-
lutionary processes including gene duplication, intragenic duplication, exon
shuffling and single base-pair substitution mediated divergence (Laudet
et al
.,
1993).
Duplications or amplifications of transcription factor genes are sometimes very
ancient as is evidenced by the limited homology still evident between nuclear fac-
tor 1 (NF1) and the protein kinase family (Mannermaa and Oikarinen, 1989). On
the other hand, some duplications have occurred during mammalian evolution
[e.g. the transcription factors
TCF1
(12q24) and
LEF1
(4q23-q25); Gastrop
et al
.,
