Hematopoiesis - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 36

2.4.1.3 E Protein Family of bHLH Transcription Factors

In mammals, the E protein family of basic helix-loop-helix (bHLH) transcription
factors that are involved in B- and T-lymphocyte development includes transcription
factors TcF3, 28 TcF4, 29 and TcF12. 30 Distinct proteins are formed by alternative
transcription initiation, in addition to 2 splice variants TcFE2

31 and TcF3 32
encoded by the E2A gene. 33 Ubiquitin conjugase UbC9 causes the degradation of
E2A proteins by the proteasome. 34
Inhibitors of DNA-binding proteins constitute a set of 4 members (ID1-ID4).
These helix-loop-helix proteins that lack a basic region prevent E proteins from
binding to DNA.
Transcription factors of the E protein family of the bHLH superclass can form:
(1) homo- or heterodimers with distinct family members that acts as transcription
activators; (2) heterodimers with class-2 bHLH proteins, subclass-A basic helix-
loop-helix protein bHLHa17, or T-cell acute lymphocytic leukemia protein-1
(TAL1) 35 and bHLHa18, or lymphoblastic leukemia-derived sequence-1 (LyL1), 36
that function as transcription activators or repressors whether they recruit coactivator
or corepressor complexes; and (3) heterodimers with any ID protein that do not bind
DNA [ 70 ]. 37

α

28 A.k.a. transcription factor E2 α , E2A immunoglobulin enhancer-binding factor E12-E47, im-
munoglobulin transcription factor ITF1, and subclass-B basic helix-loop-helix protein bHLHb21.
29 A.k.a. immunoglobulin transcription factor ITF2, SL3-3 enhancer factor SEF2, E2-2, and
bHLHb19.
30 A.k.a. human E-box-binding protein (HEB), human transcription factor HTF4, and bHLHb20.
31 Or E12.
32 Or E47.
33 Alternative transcription start sites in genes give rise to canonical (Can) and alternative (Alt)
forms of TcF4 and TcF12 proteins. Proteins of the E2A set, TcFE2 α and TcF3, as well as TcF4 Can
and TcF12 Can , possess 2 activation domains AD1 and AD2, whereas TcF4 Alt and TcF12 Alt have a
single activation domain [ 70 ]. Subtype TcF12 Alt is highly expressed by CD4 − ,CD8 − thymocytes.
34 Carboxy terminus of heat shock protein HSP70-interacting protein (CHIP) that promotes
formation of a pre-ubiquitination complex including E3-ubiquitin ligase SKP1 (S-phase-kinase-
associated protein)-cullin-1-F-box-protein complex SCFSKP2 binds E2A proteins.
35 T-cell acute lymphocytic leukemia protein-1, or stem cell leukemia factor (SCL), is involved
in the generation of hematopoietic stem cells from mesoderm during embryongenesis. In adult
mice, bHLHa17 is implicated in self-renewal of short-term repopulating hematopoietic stem cells
and development of erythrocytes and megakaryocytes, but not for maintenance of long-term
repopulating hematopoietic stem cells [ 70 ].
36 Lymphoblastic leukemia-derived sequence factor-1 heterodimerizes with E proteins to ensure
self-renewal of long-term repopulating hematopoietic stem cells [ 70 ].
37 Homo- and heterodimeric E proteins bind to E-box sequence (preferentially CACCTG E-box
sequence) of target genes and recruit transcriptional coactivators such as P300 and CBP histone
acetyltransferases and RNA polymerase-2. Heterodimers composed of E proteins and class-2
bHLH factors associate with CATATG E-box sequence of target genes and recruit coactivators
or corepressors, such as cyclin-D- and Runt-related transcription factor-1 translocated to protein-1
(Runx1T1), a.k.a. ETO corepressor (eight twenty one) and zinc finger MYND domain-containing